Bicyclic compound and use thereof

ABSTRACT

The present disclosure relates to a compound derivative containing a 6-7 bicyclic ring and use thereof. The compound according to the present invention can be effectively used in the prevention or treatment of diseases caused by PRMT5 by acting as a PRMT5 inhibitor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of PCT Application No.PCT/KR2020/013424, filed on Sep. 29, 2020, which claims the benefit andpriority to Korean Patent Application No. 10-2019-0122177, filed on Oct.2, 2019. The entire disclosures of the applications identified in thisparagraph are incorporated herein by references.

FIELD

The present disclosure relates to a compound derivative containing a 6-7bicyclic ring and use thereof. The compound according to the presentinvention can be effectively used in the prevention or treatment ofdiseases caused by protein arginine methyltransferases 5 (PRMT5) byacting as a PRMT5 inhibitor.

BACKGROUND

PRMT (protein arginine methyltransferases) are enzymes that transfermethyl groups to arginine in target proteins using the cofactor SAM(S-adenosyl methionine). Up to now, there are a total of 9 PRMT isoforms(PRMT1-9) have been known, and these are largely divided into 3 types.It has been known that PRMT1, 2, 3, 4, 6 and 8—which belong to type IPRMT—cause monomethylation and asymmetric dimethylation of arginine, andPRMT5 and PRMT9 belonging to type II PRMT induce monomethylation andsymmetric dimethylation of arginine. Meanwhile, PRMT7—which is a typeIII PRMT—mainly causes monomethylation of arginine. PRMT inducesmethylation of various substrates present in the nucleus and cytoplasm,thereby regulating important biological processes in cells such as cellproliferation, differentiation and splicing.

PRMT5 is a major arginine methyl group transfer enzyme among type IIPRMTs. It forms a functional complex with methylosome protein 50 (MEP50)to cause methylation of the target protein. PRMT5 is involved in theformation of leukemia, lymphoma, glioblastoma, lung cancer and breastcancer by methylating target proteins including histone protein in thenucleus and non-histone protein such as p53, NFκB, PI3K/AKT and CRAF.Specifically, it is well known that cancer formation by PRMT5 occurs asthe proliferation, differentiation, invasion and migration of tumorcells are promoted. In addition, according to several reports, it isknown that the higher the expression of PRMT5 is, the poorer theprognosis of cancer patients is. To the contrary, it has been observedthat when the expression of PRMT5 is inhibited, the proliferation oftumor cells can be suppressed.

Meanwhile, it has been recently reported that diseases other than cancercan also be mediated by PRMT5.

SUMMARY

An object of the present invention is to provide a novel compound basedon a 6-7 bicyclic ring showing excellent PRMT5 inhibitory effect, or anoptical isomer, a stereoisomer or an isotopic variant thereof, or apharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceuticalcomposition comprising the above novel compound based on a 6-7 bicyclicring, or an optical isomer, a stereoisomer or an isotopic variantthereof, or a pharmaceutically acceptable salt thereof as an activeingredient.

To achieve the above object, the present invention provides a compoundrepresented by the following Formula 1, or an optical isomer, astereoisomer or an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof:

wherein

X¹ and X² are each independently carbon or nitrogen;

Y is carbon, oxygen or nitrogen;

Z is carbon;

n is an integer of 0 or 1;

m is an integer of 0 to 2;

is a single bond or a double bond;

R¹ is -D-R¹⁰; wherein D is a direct bond, —O—, —C(═O)—, —C≡C— or—CR¹¹R¹²—; R¹⁰ is hydrogen, halo, hydroxy, cyano, alkyl, hydroxyalkyl,haloalkyl, haloalkylsulfonate, dialkylamino, alkylaminoalkyl,dialkylaminoalkyl, dialkylaminocarbonylalkyl, saturated or unsaturatedcarbocyclyl, saturated or unsaturated heterocyclyl, saturated orunsaturated carbocyclyl-alkyl, or saturated or unsaturatedheterocyclyl-alkyl; R¹¹ and R¹² are each independently hydrogen, hydroxyor alkyl; the carbocycle or heterocycle may be substituted with one ormore substituents selected from hydroxy, halo, oxo, formyl (—CHO),nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl,haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl,alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl,(alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl andheterocyclyl-alkyl;

R² is hydrogen or alkyl;

R³ is hydrogen or alkyl;

R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen or alkyl;

R⁸ is hydrogen, halo, alkyl, alkoxy or amino; and

R⁹ is hydrogen, halo or alkyl.

Unless indicated otherwise, the term “alkyl” used herein, either aloneor in combination with additional terms (for example, haloalkyl), refersto a radical of a saturated aliphatic hydrocarbon group having, forexample 1 to 7 carbon atoms of a linear or branched chain. For example,the alkyl may include such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1-ethylpropyl and1,2-dimethylpropyl, but is not limited thereto.

Unless indicated otherwise, the term “alkoxy” used herein refers toalkyloxy having, for example 1 to 7 carbon atoms.

Unless indicated otherwise, the term “halo” used herein, either alone orin combination with additional terms (for example, haloalkyl), refers toa radical of fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

Unless indicated otherwise, the term “haloalkyl” used herein refers toan alkyl defined as above in which one or more of the hydrogen atoms arereplaced with one or more same or different halogen atoms. Exemplaryhaloalkyl may include —CH₂Cl, —CH₂CF₃, —CH₂CCl₃ or perfluoroalkyl (e.g.,—CF₃).

Unless indicated otherwise, the term “oxo” used herein refers to thegroup of ═O (that is, oxygen having a double bond). For example,1-oxo-ethyl group is an acetyl group.

Unless indicated otherwise, the term “hydroxyalkyl” used herein refersto an alkyl in which one or more of the hydrogen atoms are replaced withone or more hydroxy (—OH) groups. For example, it may include that thehydrogen atoms are replaced with 2 or 3 hydroxy groups.

Unless indicated otherwise, the term “saturated or unsaturatedcarbocyclyl” used herein refers to a radical of a hydrocarbon that isunsaturated or partially or fully saturated, forming a single or fusedcyclic ring having, for example 3 to 24 carbon atoms. Specifically, thecarbocyclyl may have 3 to 10 carbon atoms. The carbocycle may include abridged structure or a spiro structure. In addition, the unsaturatedcarbocycle may include an aromatic hydrocarbon such as aryl.

According to one embodiment of the present invention, the carbocycle maybe cyclohexane, cyclohexene, cyclopropane, cyclobutane or cyclopentane,but is not limited thereto.

Unless indicated otherwise stated, the term “saturated or unsaturatedheterocyclyl” used herein refers to 3- to 24-membered hydrocarbon thatis unsaturated or partially or fully saturated, forming a single orfused cyclic ring, and having one or more heteroatoms, for example 1 to8 heteroatoms selected from the group consisting of nitrogen (N), oxygen(O) and sulfur (S) Specifically, the heterocyclyl may be a 4- to10-membered hydrocarbon having 1 to 3 hetero atoms. The heterocycle mayinclude a bridged structure or a spiro structure. In addition, theunsaturated heterocyclyl may include an aromatic hydrocarbon such asheteroaryl.

According to one embodiment of the present invention, the heterocyclemay be tetrahydropyridine, dihydropyridine, piperidine, dihydropyran,tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine,morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole,pyrrolidine, oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl,tetrahydrofuran, 8-azabicyclo[3.2.1]octane, piperazine,2-azaspiro[3.3]heptane, 2-oxa-7-azaspiro[3.4]octane,2-azabicyclo[2.2.1]heptane, 3-oxa-8-azabicyclo[3.2.1]octane,3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine,3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2]-a]pyrazine, pyrimidine, pyrazole,2-oxa-7-azaspiro[3.5]nonane or oxetane, but is not limited thereto.

According to one embodiment of the present invention, in the aboveFormula 1, X¹ and X² are each independently CH or N.

According to one embodiment of the present invention, in the aboveFormula 1, Y is CH₂, 0 or NH, when n is 0; and Y is CH or N, when n is1.

According to one embodiment of the present invention, in the aboveFormula 1, Z is CH₂ or CH, when m is 0; Z is CH or C, when m is 1; and Zis C, when m is 2.

According to one embodiment of the present invention, in the aboveFormula 1,

is a single bond or a double bond.

According to one embodiment of the present invention, in the aboveFormula 1, R¹ is -D-R¹⁰; wherein D is a direct bond, —O—, —C(═O)—, —C≡C—or —CR¹¹R¹²—.

According to one embodiment of the present invention, in the aboveFormula 1, R¹⁰ is hydrogen, halo, hydroxy, cyano, C₁-C₇ alkyl,hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, halo-C₁-C₇ alkylsulfonate,di(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino-C₁-C₇ alkyl, di(C₁-C₇alkyl)amino-C₁-C₇ alkyl, di(C₁-C₇ alkyl)aminocarbonyl-C₁-C₇ alkyl,saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated,4- to 10-membered heterocyclyl, saturated or unsaturated C₃-C₁₀carbocyclyl-C₁-C₇ alkyl, or saturated or unsaturated, 4- to 10-memberedheterocyclyl-alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R¹¹ and R¹² are each independently hydrogen, hydroxy or C₁-C₇alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, the carbocycle or heterocycle may be substituted with 1 to 5substituents selected from hydroxy, halo, oxo, formyl, nitrile, C₁-C₇alkyl, C₁-C₇ alkoxy, hydroxy-C₁-C₇ alkyl, hydroxyhalo-C₁-C₇ alkyl, C₁-C₇alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, nitrile-C₁-C₇ alkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkylthiocarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇alkylcarbonyl, saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated orunsaturated C₃-C₁₀ carbocyclylcarbonyl, (C₁-C₇ alkyl)(halo-C₁-C₇alkyl)amino, (C₁-C₇ alkyl)(saturated or unsaturated, 4- to 10-memberedheterocyclyl)amino, saturated or unsaturated, 4- to 10-memberedheterocyclyl and saturated or unsaturated, 4- to 10-memberedheterocyclyl-C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R² is hydrogen or C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R³ is hydrogen or C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen or C₁-C₇alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R⁸ is hydrogen, halo, C₁-C₇ alkyl, C₁-C₇ alkoxy or amino.

According to one embodiment of the present invention, in the aboveFormula 1, R⁹ is hydrogen, halo or C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, X¹ and X² are each independently CH or N; Y is CH₂, 0 or NH,when n is 0; Y is CH or N, when n is 1; Z is CH₂ or CH, when m is 0; Zis CH or C, when m is 1; Z is C, when m is 2; and

is a single bond or a double bond.

According to one embodiment of the present invention, in the aboveFormula 1, R¹ is -D-R¹⁰; wherein D is a direct bond, —O—, —C(═O)—, —C≡C—or —CR¹¹R¹²—; R¹⁰ is hydrogen, halo, hydroxy, cyano, C₁-C₇ alkyl,hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, halo-C₁-C₇ alkylsulfonate,di(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino-C₁-C₇ alkyl, di(C₁-C₇alkyl)amino-C₁-C₇ alkyl, di(C₁-C₇ alkyl)aminocarbonyl-C₁-C₇ alkyl,saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated,4- to 10-membered heterocyclyl, saturated or unsaturated C₃-C₁₀carbocyclyl-C₁-C₇ alkyl, or saturated or unsaturated, 4- to 10-memberedheterocyclyl-alkyl; and R¹¹ and R¹² are each independently hydrogen,hydroxy or C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, R¹⁰ is halo, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇alkyl, saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated orunsaturated, 4- to 10-membered heterocyclyl, or saturated orunsaturated, 4- to 10-membered heterocyclyl-alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, the carbocycle or heterocycle may be substituted with 1 to 5substituents selected from hydroxy, halo, oxo, formyl, nitrile, C₁-C₇alkyl, C₁-C₇ alkoxy, hydroxy-C₁-C₇ alkyl, hydroxyhalo-C₁-C₇ alkyl, C₁-C₇alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, nitrile-C₁-C₇ alkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkylthiocarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇alkylcarbonyl, saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated orunsaturated C₃-C₁₀ carbocyclylcarbonyl, (C₁-C₇ alkyl)(halo-C₁-C₇alkyl)amino, (C₁-C₇ alkyl)(saturated or unsaturated, 4- to 10-memberedheterocyclyl)amino, saturated or unsaturated, 4- to 10-memberedheterocyclyl and saturated or unsaturated, 4- to 10-memberedheterocyclyl-C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, the carbocycle or heterocycle may be substituted with 1 to 5substituents selected from hydroxy, halo, formyl, C₁-C₇ alkyl,hydroxy-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, saturatedor unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated C₃-C₁₀carbocyclylcarbonyl, (C₁-C₇ alkyl)(halo-C₁-C₇ alkyl)amino, (C₁-C₇alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)aminoand saturated or unsaturated, 4- to 10-membered heterocyclyl-C₁-C₇alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, the heterocycle may be substituted with 1 or 2 substituentsselected from hydroxy, halo, formyl, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl,C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, C₁-C₇ alkylcarbonyl, C₁-C₇alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, saturated or unsaturatedC₃-C₁₀ carbocyclyl, saturated or unsaturated C₃-C₁₀ carbocyclylcarbonyland saturated or unsaturated, 4- to 10-membered heterocyclyl-C₁-C₇alkyl.

According to one embodiment of the present invention, in the aboveFormula 1, the carbocycle may be substituted with 1 or 2 substituentsselected from halo-C₁-C₇ alkyl, (C₁-C₇ alkyl)(halo-C₁-C₇ alkyl)amino and(C₁-C₇ alkyl)(saturated or unsaturated, 4- to 10-memberedheterocyclyl)amino.

According to one embodiment of the present invention, in the aboveFormula 1, R¹ is -D-R¹⁰; wherein D is a direct bond; R¹⁹ is hydrogen,halo, cyano, C₁-C₇ alkyl, halo-C₁-C₇ alkyl,di(C₁-C₇alkyl)amino-C₁-C₇alkyl, saturated or unsaturated, 4- to10-membered heterocyclyl, saturated or unsaturated C₃-C₁₀ carbocyclyl,or saturated or unsaturated, 4- to 10-membered heterocyclyl-alkyl; andthe heterocycle may be substituted with 1 or 2 substituents selectedfrom hydroxy, halo, formyl, C₁-C₇ alkyl, C₁-C₇ alkoxy, hydroxy-C₁-C₇alkyl, halo-C₁-C₇ alkyl, nitrile-C₁-C₇ alkyl, C₁-C₇ alkylcarbonyl, C₁-C₇alkoxy-C₁-C₇ alkyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, andsaturated or unsaturated, 4- to 10-membered heterocyclyl.

According to one embodiment of the present invention, in the aboveFormula 1, R² is hydrogen or C₁-C₇ alkyl; R³ is hydrogen or C₁-C₇ alkyl;R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen or C₁-C₇ alkyl; R⁸ ishydrogen, halo, C₁-C₇alkyl, C₁-C₇alkoxy or amino; and R⁹ is hydrogen,halo or C₁-C₇ alkyl.

According to one embodiment of the present invention, in the aboveFormula 1,

is a single bond.

According to one embodiment of the present invention, in the aboveFormula 1, the heterocycle is a saturated or unsaturated, 4- to8-membered hydrocarbon having 1 or 2 heteroatoms selected from N and 0.

According to one embodiment of the present invention, in the aboveFormula 1, the heterocycle is selected from the group consisting oftetrahydropyridine, dihydropyridine, piperidine, dihydropyran,tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine,morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, oxazepane,2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, tetrahydrofuran,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane,2-oxa-7-azaspiro[3.4]octane, 2-azabicyclo[2.2.1]heptane,3-oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine,3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2]-a]pyrazine, pyrimidine, pyrazole,2-oxa-7-azaspiro[3.5]nonane, and oxetane.

According to one embodiment of the present invention, in the aboveFormula 1, the heterocycle is selected from the group consisting oftetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran,pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine,3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole,and oxetane.

According to one embodiment of the present invention, in the aboveFormula 1, the carbocycle is selected from the group consisting ofcyclohexane, cyclohexene, cyclopropane, cyclobutane, and cyclopentane.

According to one embodiment of the present invention, in the aboveFormula 1, D is a direct bond, —O—, —C(═O)— or —C≡C—; R¹⁰ is halo, C₁-C₇alkyl, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, saturated or unsaturatedC₃-C₁₀ carbocyclyl, saturated or unsaturated, 4- to 10-memberedheterocyclyl, or saturated or unsaturated, 4- to 10-memberedheterocyclyl-alkyl; the carbocycle or heterocycle may be substitutedwith 1 to 5 substituents selected from hydroxy, halo, formyl, C₁-C₇alkyl, hydroxy-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl,C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl,saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturatedC₃-C₁₀ carbocyclylcarbonyl, (C₁-C₇alkyl)(halo-C₁-C₇alkyl)amino, (C₁-C₇alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)amino,and saturated or unsaturated, 4- to 10-membered heterocyclyl-C₁-C₇alkyl; the heterocycle is selected from the group consisting oftetrahydropyridine, dihydropyridine, piperidine, tetrahydropyran,pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine, morpholine,3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole,and oxetane; and the carbocycle is selected from the group consisting ofcyclohexane, cyclohexene, and cyclopropane.

Representative examples of the compound of Formula 1 according to thepresent invention may include compounds shown in Table 1, but are notlimited thereto.

TABLE 1 No. Compound Name 14-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one 22-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2-benzazepin-1-one 32-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2-benzazepin-1-one 42-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one 54-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 62-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one 72-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-ethoxy-4,5-dihydro-3H-2-benzazepin-1-one 8[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-yl]trifluoromethanesulfonate 92-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-carbonitrile 104-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 114-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propyl-2,3-dihydro-1,4-benzoxazepin-5-one 124-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydro-1,4-benzoxazepin-5-one 134-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzoxazepin-5-one 14 tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate 154-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 168-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 178-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 184-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 194-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 204-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 214-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yl-2,3-dihydro-1,4-benzoxazepin-5-one 224-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 234-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 244-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 254-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 268-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 274-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 284-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 294-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 304-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-methylmorpholin-4-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 318-[(4,4-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 324-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 334-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3,5-dimethyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 348-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-ylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one354-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxypyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 364-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 374-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 384-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methoxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 394-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 404-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-3-methyl-pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 414-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)morpholin-4-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 428-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 434-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 444-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 454-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 464-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 474-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 484-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethylpyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 494-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 504-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(methoxymethyl)pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 514-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoropyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 528-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 538-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 544-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one 554-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 564-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 574-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 584-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 598-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 608-[(2,3-difluoro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 614-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-fluoro-3-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 624-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 634-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 644-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yloxy-2,3-dihydro-1,4-benzoxazepin-5-one 654-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydropyran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 668-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 674-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 684-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 694-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 708-[(1-acetyl-4-piperidyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 714-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,2,2-trifluoroethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 724-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(dimethylamino)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 734-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-morpholinoethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one 744-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(2-oxopyrrolidin-1-yl)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 754-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 764-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-oxo-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 77 tert-butyl4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carboxylate 788-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 798-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 808-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 818-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 828-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 838-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 844-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-propanoylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 858-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 86 methyl3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carboxylate 874-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 884-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 894-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 908-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 918-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 924-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 934-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 944-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 954-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 964-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-[1-(oxetan-3-yl)azetidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 974-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 984-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 994-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 1004-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one 1014-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1024-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1034-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1044-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1054-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1064-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1074-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1084-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1094-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1104-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 1114-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-1,4-benzoxazepin-5-one 1124-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-1,4-benzoxazepin-5-one 1134-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylmethoxy)-3H-1,4-benzoxazepin-5-one 1148-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 1154-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one 1164-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzodiazepin-5-one 1178-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1188-(cyclohexen-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1194-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-[4-(trifluoromethyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one 120 tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2,3-dihydro-1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate1218-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1228-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1238-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1248-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1254-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1264-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1278-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1284-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahydrofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1294-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1304-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1314-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1324-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one 1334-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)rnethoxy]-2,3-dihydro-1,4-benzodiazepin-5-one 1344-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1354-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride 1364-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1374-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1384-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(2-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one dihydrochloride 1394-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1404-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride 1414-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 142(2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 143(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1444-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one 1454-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one 146(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1474-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1482-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one 1494-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1504-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one 1518-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1524-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f][1,4]oxazepin-5-one 1538-chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one 1547-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one 1557-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one 1568-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one 1578-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one 1588-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1,4-benzodiazepin-2,5-dione 1592-[4-[[4-(2R)-3-(3,4,-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3,-dihydro-1,4,-benzoxazepin-8-yl]-1-piperidyl]acetonitrile 1608-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1618-[[1-(2,2-difluoroacetyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1624-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1634-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1644-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one 1654-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[[1-[(3-methyloxetan-3-yl)methyl]-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1664-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoazepin-8-yl]oxy]piperidine-1-carbonitrile 1678-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 1683-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carbaldehyde 1694-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]methyl]piperazin-1-carbaldehyde 1704-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one 1714-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1724-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1738-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1748-[(2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1754-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1764-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1778-(3,3-difluoropyrrolidin-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1784-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazin-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1794-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrrolidin-1-ylmethyl)-3H-1,4-benzoxazepin-5-one 1808-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 1814-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carbaldehyde 1824-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]-3H-1,4-benzoxazepin-5-one 1834-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-7-azaspiro[3.4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one 1844-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1854-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-[3-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1864-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1874-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1888-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1894-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1904-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1914-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1924-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one 1938-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one1944-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one 1958-(2,2-difluoromorpholin-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1968-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 1974-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-piperidylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one 1984-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 1994-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl(methyl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one 200(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4-piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 201(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)azetidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 202(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)-4-piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2034-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-3H-1,4-benzoxazepin-5-one 2044-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one 2054-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,5-dimethylmorpholin-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 2064-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2074-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2084-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2094-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one 2108-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one2114-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin-2-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one 2124-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2134-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2144-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propanoyl-2,3-dihydro-1,4-benzoxazepin-5-one 2154-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2168-(cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2178-(cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2184-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 219(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 220(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one2214-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2224-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2234-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-pynyl)-2,3-dihydro-1,4-benzoxazepin-5-one 224(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2254-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2264-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(4-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2274-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(3-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2284-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybu-1-tynyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2294-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)pro-1-pynyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2304-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2314-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 2324-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 2334-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one 2344-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one 2354-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[(3R)-1-methyl-3-piperidyl]oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one 2364-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2374-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2384-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 2394-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-fluoro-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one 240(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-ethoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 241(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-hydroxy]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one242(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one2434-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-pyridyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2444-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-methoxy-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one 245(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2464-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one 2474-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-3H-pyrido[3,2-f][1,4]oxazepin-5-one2484-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one 2494-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 250(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2514-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 252(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one 2534-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride 2544-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride 255(2R)-4-[(2R)-3-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride 2568-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one2574-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2584-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-hydroxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2594-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-methoxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2604-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(3-hydroxy-3-methyl-pyrrolidin-1-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one 261(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride 2624-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one 2634-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 264(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 2654-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3R)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 2664-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3S)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 267(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2S)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one268(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2R)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2698-[cyclopropyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2708-[cyclopentyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one 2714-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 2724-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 273(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one 274(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one 2754-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one 276(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-2-methyl-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one277(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

Since the compounds according to the present invention may have anasymmetric carbon center and an asymmetric axis or an asymmetric plane,they may exist as substantially pure enantiomers, such as R and Senantiomers, as well as all optical and stereoisomeric forms includingmixture racemates, and all isomers and compounds thereof are within thescope of the present invention. With respect to a pure enantiomer, theenantiomeric excess of such enantiomer and pharmaceutically acceptablesalt thereof represented by Formula 1 may be preferably 60% ee or more,more preferably 95% ee ore more, and most preferably 98% ee or more.

The term “ee” refers to an enantiomeric excess. For example, oneenantiomer in a particular compound is present as a mixture ofenantiomers in the compound in a larger amount than the otherenantiomers. Enantiomerically enriched forms may include enantiomericcompounds of a particular compound in which a single enantiomericconcentration in the enantiomeric mixture of the particular compound isat least 50%, more typically at least 60%, 70%, 80%, or 90%, or more(e.g., >95%, >97%, >98%, >99%, >99.5%) with respect to other enantiomersof the compound.

Herein, unless stated otherwise, the compound represented by Formula 1is used as a meaning including all of compound represented by Formula 1,an optical isomer, a stereoisomer, an isotopic variant thereof, and apharmaceutically acceptable salt thereof.

Herein the term “isotopic variant” refers to a compound that containsunnatural proportions of isotopes at one or more of the atoms thatconstitute such compound. For example, an isotopic variant of a compoundmay be radiolabeled; hydrogen atom may be selected from hydrogen,deuterium and tritium; and may contain carbon-13 (¹³C), nitrogen-15(¹⁵N) or the like.

The compound of Formula 1, or an optical isomer, a stereoisomer or anisotopic variant thereof according to the present invention may form apharmaceutically acceptable salt. The pharmaceutically acceptable saltsinclude acid or base addition salts and their stereochemical isomersform. The salt may include any salt that maintains the activity of aparent compound in a subject to be administered and does not cause anyundesirable effect, but is not limited thereto. The salts includeinorganic salts and organic salts, and may be acid addition salts—forexample, acetic acid, nitric acid, aspartic acid, sulfonic acid,sulfuric acid, maleic acid, glutamic acid, formic acid, succinic acid,phosphoric acid, phthalic acid, tannic acid, tartaric acid, hydrobromicacid, propionic acid, benzenesulfonic acid, benzoic acid, stearic acid,ethanesulfonic acid, lactic acid, bicarbonic acid, bisulfuric acid,bitartaric acid, oxalic acid, butylic acid, calcium edatate, camsylicacid, carbonic acid, chlorobenzoic acid, citric acid, edetic acid,toluenesulfonic acid, edicylinic acid, ecylinic acid, fumaric acid,gluceptic acid, pamoic acid, gluconic acid, glycollarsanylic acid,methyl nitrate, polygalacturonic acid, hexyllisorcynonic acid, malonicacid, hydrabamic acid, hydrochlorinic acid, hydroiodic acid,hydroxynaphtholic acid, isethionic acid, lactobionic acid, mandelicacid, estolinic acid, mucic acid, naphthenic acid, muconic acid,p-nitromethanesulfonic acid, hexamic acid, pantothenic acid,monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylicacid, sulfamine acid, sulfanilic acid, methanesulfonic acid or theoclicacid. In addition, examples of basic salts include alkali and alkalineearth metal salts such as ammonium salts, lithium salts, sodium salts,potassium salts, magnesium salts, and calcium salts, salts havingorganic bases such as benzathine, N-methyl-D-glucamine, and hydrabaminesalts, and salts having amino acids such as arginine and lysine. Inaddition, the salt form may be converted into a free form by treatmentwith an appropriate base or acid. As used herein, the term “additionalsalt” may be taken to include solvates obtainable from any of thecompound represented by Formula 1 and salts thereof. Examples of thesesolvates are hydrates or alcoholates.

Terms and abbreviations used in the present specification have theiroriginal meanings unless stated otherwise.

The present invention also provides a method for preparing a compound ofFormula 1. Hereinafter, a method of preparing the compound of Formula 1will be described based on an exemplary reaction scheme for betterunderstanding of the present invention. However, it should be construedthat those of ordinary skill in the art may prepare the compound ofFormula 1 by various methods using known compounds based on thestructure of Formula 1 or compounds that may be easily preparedtherefrom, and be construed that all the methods may be included in thescope of the present invention. That is, the compound of Formula 1 maybe prepared by arbitrarily combining several synthesis methods describedin the present specification or disclosed in the prior art, and thus thefollowing description related to the method of preparing the compound ofFormula 1 is merely illustrative, and if necessary, the order of unitoperations may be selectively changed, and the scope of the method ofpreparing the present invention is not limited thereto.

In a general synthesis method, an intermediate 3 can be obtained fromthe starting material 2 by Schmidt reaction using sodium azide under anacidic condition. From this compound, an intermediate 4 into whichoxirane has been introduced is obtained through a substitution reaction,and a final compound 1a can be obtained through addition reaction oftetrahydroisoquinoline.

As another synthesis method, a final compound 1b in which alkyl andalkenyl groups are substituted can be obtained by a Suzuki-couplingreaction under a palladium condition using compound 5 as a startingmaterial.

In still another synthesis method, as in Scheme 3, compound 5 is used asa starting material and an intermediate 6 obtained by substituting abromine group with a hydroxy group using potassium hydroxide under apalladium condition was obtained, and then a final compound 1c—in whichthe ether group was substituted through a substitution reaction—can beobtained.

According to another aspect of the present invention, there is provideda pharmaceutical composition for the prevention or treatment of adisease associated with PRMT5 inhibition comprising a therapeuticallyeffective amount of the compound, or optical isomer, stereoisomer orisotopic variant thereof, or pharmaceutically acceptable salt thereof asan active ingredient, together with a pharmaceutically acceptablecarrier. In addition, prodrugs having various forms that are convertedto a compound of Formula 1 as desired in vivo are also within the scopeof the present invention. The pharmaceutical composition may furtherinclude one or more additives selected from the group consisting of apharmaceutically acceptable carrier, diluent and adjuvant.

As used herein, the term “treatment” refers to the interruption, delayor alleviation of disease progression when used in a subject having asymptom.

As used herein, the term “prevention” refers to reduce the possibilityof disease or eliminate the possibility of disease.

As used herein, the term “pharmaceutical composition” may include otherchemical components, such as carriers, diluents, excipients, and thelike in addition to the active compounds according to the presentinvention. Accordingly, the pharmaceutical composition may include apharmaceutically acceptable carrier, diluent, excipient, or acombination thereof, if necessary. The pharmaceutical compositionfacilitates administration of the active compound into the organism. Avariety of techniques for administering pharmaceutical compositionscomprising a compound are known, in which the techniques includes oral,injection, aerosol, parenteral, and topical administration, but notlimited thereto. In addition, the pharmaceutical composition may besterilized, may further include an adjuvant such as a preservative, astabilizer, a hydrating or an emulsifying accelerator, a salt forosmotic pressure regulation, and/or a buffer, may further include othertherapeutically useful substances, and may be formulated according toconventional methods of mixing, granulating or coating.

As used herein, the term “carrier” refers to a compound that facilitatesinjection of a compound into a cell or tissue. For example,dimethylsulfoxide (DMSO) is a common carrier for easy input of a largeamount of organic compounds into cells or tissues of an organism.

As used herein, the term “diluent” refers to a compound that stabilizesthe biologically active form of the compound of interest, and is dilutedin water that dissolves the compound. The salt dissolved in the bufferis used as a diluent in the art. A commonly used buffer isphosphate-buffered saline that imitates the salt form of a human bodysolution. Since the buffer salt is capable of controlling the pH of thesolution at low concentrations, the buffer diluent rarely modifies thebiological activity of the compound.

As used herein, the term “pharmaceutically acceptable” refers to aproperty that does not damage biological activity and physicalproperties of a compound.

In addition, the pharmaceutical composition may be a composition for theprevention and/or treatment of diseases associated with PRMT5inhibition. The diseases associated with the PRMT5 inhibition may be,for example, cancer, blood disease, autoimmune disease, inflammatorydisease or neurodegenerative disease, and may include any disease knownto be related to PRMT5.

The cancer includes, but is not limted to, acoustic neuroma,adenocarcinoma, adrenal cancer, anal cancer, angiosarcoma, benignmonoclonal gammaglobulinopathy, cholangiocarcinoma, bladder cancer,breast cancer, brain cancer, lymphoma, multiple myeloma, lacrimal glandtumor, bronchial cancer, cervical cancer, craniopharyngioma, colorectalcancer, epithelial carcinoma, epithelial cell tumor, endothelialsarcoma, endometrial cancer, esophageal cancer, Barrett'sadenocarcinoma, Ewing's sarcoma, eye cancer, gallbladder cancer, gastriccancer, gastrointestinal stromal tumor (GIST), head and neck cancer,oral cancer (oral squamous cell carcinoma, OSCC), throat cancer,hematopoietic cancer, hemangioblastoma, inflammatory myofibroblasttumor, immune cell amyloidosis, kidney cancer, liver cancer, lungcancer, myelodysplastic syndrome (MDS), mesothelioma, myeloproliferativedisorder (MPD), chronic idiopathic myelofibrosis, chronic myelogenousleukemia (CML), chronic neutrophilic leukemia (CNL), neuroblastoma,neurofibroma, neuroendocrine cancer, osteosarcoma, ovarian cancer,papillary adenocarcinoma, pancreatic cancer, penile cancer, prostatecancer, rectal cancer, rhabdomyosarcoma, salivary gland cancer, skincancer, small intestine cancer, soft tissue sarcoma, thyroid cancer,urethral cancer, vaginal cancer and vulvar cancer. The brain cancer mayinclude, but is not limited to, meningioma, glioma, medulloblastoma,glioblastoma and brain metastasis cancer.

The blood disease may be hemoglobinemia or sickle cell anemia, but isnot limited thereto.

The autoimmune disease may include, but is not limited to, rheumatoidarthritis, spinal arthritis, gouty arthritis, degenerative jointdisease, osteoarthritis, systemic lupus erythematosus, multiplesclerosis, psoriatic arthritis, juvenile arthritis, asthma,atherosclerosis, osteoporosis, bronchitis, tendinitis, psoriasis,eczema, burns, dermatitis, pruritus, enuresis, eosinophilic disease,peptic ulcer, localized enteritis, diverticulitis, gastrointestinalbleeding, eosinophilic esophagitis, eosinophilic gastritis, eosinophilicgastroenteritis and eosinophilic colitis.

The inflammatory disease may include, but is not limited to,acne-related inflammation, aplastic anemia, hemolytic autoimmune anemia,rhinitis, asthma, polyarteritis, temporal arteritis, periarteritisnodosa, Takayasu's arteritis, crystalline arthritis, osteoarthritis,psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoidarthritis, amyotrophic lateral sclerosis, autoimmune disease, allergicor allergic reaction, atherosclerosis, bronchitis, bursitis, chronicprostatitis, conjunctivitis, chronic obstructive pulmonary disease,dermatitis, type I diabetes, type 2 diabetes, psoriasis, eczema, eczemahypersensitivity reaction, burn, dermatitis, pruritus, endometriosis,infection, ischemic heart disease, glomerulonephritis, gingivitis,irritability, migraine, tension headache, postoperative intestinalobstruction, intestinal obstruction during sepsis, idiopathicthrombocytopenia purpura, bladder pain syndrome, peptic ulcer, localizedenteritis, diverticulitis, gastric bleeding, eosinophilic esophagitis,eosinophilic gastritis, eosinophilic gastroenteritis, eosinophiliccolitis, gastritis, diarrhea, gastroesophageal reflux disease, Crohn'sdisease, ulcerative colitis, collagenous colitis, lymphocytic colitis,ischemic colitis, bypass colitis, Behcet's syndrome, indeterminatecolitis, inflammatory bowel syndrome (IBS), lupus, ecchymosis,myasthenia gravis and myocardial ischemia.

The neurodegenerative disease may include, but is not limited to, motorneuron disease, Pick's disease, Alzheimer's disease, AIDS-relateddementia, Parkinson's disease, amyotrophic lateral sclerosis, retinalpigmentation, spinal muscular atrophy and cerebellar degeneration.

The pharmaceutical composition may be formulated in various oral orparenteral dosage forms. For example, the pharmaceutical composition maybe formulated into any dosage form for oral administration, such astablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers,syrups, granules or elixirs. The formulation for oral administration mayinclude, for example, a pharmaceutically acceptable carrier, such as adiluent, such as lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, and/or glycine, or a lubricant, such as silica, talc, stearicacid, magnesium or calcium salt thereof, and/or polyethylene glycol, inaddition to the active ingredient, according to the typicalconfiguration of each formulation.

In addition, when the formulation for oral administration is a tablet,the formulation may include a binder such as magnesium aluminumsilicate, starch paste, gelatin, tragacanth, methylcellulose, sodiumcarboxymethyl cellulose, and/or polyvinylpyrrolidine, and optionally,may include a disintegrant such as starch, agar, alginic acid or asodium salt thereof, a boiling mixture, and/or an absorbent, a colorant,a flavoring agent, or a sweetening agent.

When the pharmaceutical composition is formulated into a parenteraldosage form, the pharmaceutical composition may be administered by aparenteral administration method such as subcutaneous injection,intravenous injection, intramuscular injection or intrathoracicinjection. The pharmaceutical composition may be prepared as a solutionor a suspension by mixing an active ingredient—i.e., a compound ofFormula 1, or an optical isomer, a stereoisomer or an isotopic variantthereof, or a pharmaceutically acceptable salt thereof, with astabilizer or a buffer in water, and the solution or the suspension maybe prepared as a unit dosage form of an ampoule or a vial.

In addition, the pharmaceutical composition may be sterilized or furtherinclude adjuvants such as preservatives, stabilizers, hydrating agentsor emulsification accelerators, salts and/or buffers for controllingosmotic pressure, or other therapeutically useful agents, and may beformulated according to a conventional method of mixing, granulating orcoating.

The active ingredient—i.e., a compound of Formula 1, or an opticalisomer, a stereoisomer or an isotopic variant thereof, or apharmaceutically acceptable salt thereof may be included in thepharmaceutical composition in an effective amount of 0.1 to 500 mg/kg(body weight), preferably 0.5 to 100 mg/kg (body weight) per day, withrespect to mammals including humans, and the pharmaceutical compositionmay be divided once or twice a day and administered via an oral orparenteral route.

According to the present invention, there are provided compounds basedon a 6-7 bicyclic ring which exhibit excellent PRMT5 inhibitory effect,or optical isomers, stereoisomers or isotopic variants thereof, orpharmaceutically acceptable salts thereof. Therefore, such compounds, oroptical isomers, stereoisomers or isotopic variants thereof, orpharmaceutically acceptable salts thereof, can be effectively used toprevent or treat diseases associated with PRMT5 inhibition such ascancer, blood diseases, autoimmune diseases, inflammatory diseases orneurodegenerative diseases.

In addition, the compounds according to the present invention, oroptical isomers, stereoisomers or isotopic variants thereof, orpharmaceutically acceptable salts thereof, may have improved blood-brainbarrier permeability, superior efficacy or improved pharmacokineticproperties.

DETAILED DESCRIPTION

Hereinafter, the present invention is explained in more detail with thefollowing examples. However, it must be understood that the protectionscope of the present disclosure is not limited to the examples.

Example 1: Synthesis of4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one

Example 1-1: Synthesis of8-methoxy-4-(oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

8-Methoxy-3,4-dihydro-2H-1,4-benzoxazepin-5-one (97 mg, 0.5 mmol) wasdissolved in dimethylformamide, and 60% sodium hydride (30 mg, 0.75mmol) was added thereto under ice bath. After the reaction solution wasstirred at 0° C. for 30 minutes, epibromohydrin (0.056 mL, 0.65 mmol)was slowly added thereto, and the mixture was stirred at roomtemperature for 2 hours. The reaction was terminated by the addition ofmethanol. After adding ethyl acetate, the reaction mixture was washedwith a saturated aqueous ammonium chloride solution and a saturatedaqueous sodium chloride solution, and the organic layer was dried overanhydrous magnesium sulfate. The solvent was removed by evaporationunder reduced pressure, and the obtained compound was used in the nextreaction without additional purification.

Example 1-2: Synthesis of4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one

The starting material obtained in Example 1-1 was dissolved in 3 mL ofisopropanol, and tetrahydroisoquinoline (0.06 mL, 0.5 mmol) was addedthereto and stirred at 80° C. for 12 hours. The temperature was loweredto room temperature temperature, and the oily liquid obtained byconcentrating the solvent was purified by flash chromatography to obtainthe transparent and sticky solid compound. NMR data about the obtainedtitle compound are as follows:

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.20-7.00 (m,4H), 6.75 (dd, J=8.8, 2.5 Hz, 1H), 6.58 (d, J=2.5 Hz, 1H), 4.48 (t,J=5.0 Hz, 2H), 4.23 (q, J=8.2, 6.4 Hz, 1H), 3.98 (dd, J=13.9, 3.6 Hz,1H), 3.84 (s, 3H), 3.81-3.68 (m, 4H), 3.42 (dd, J=13.9, 7.7 Hz, 1H),2.97-2.85 (m, 4H), 2.69-2.60 (m, 2H).

Example 2: Synthesis of2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2-benzazepin-1-one

7-Methoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting materialwas used in the same manner as in Example 1 to obtained the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.42 (d, J=8.5 Hz, 1H), 6.99 (dd,J=20.3, 3.4 Hz, 4H), 6.78 (dd, J=8.7, 2.6 Hz, 1H), 6.69 (d, J=2.5 Hz,1H), 4.17-4.08 (m, 1H), 3.79 (dd, J=13.9, 3.8 Hz, 1H), 3.73 (s, 3H),3.71 (s, 2H), 3.35-3.23 (m, 3H), 2.88-2.79 (m, 4H), 2.68 (t, J=7.1 Hz,2H), 2.64-2.52 (m, 2H), 2.02 (p, J=7.0 Hz, 2H).

Example 3: Synthesis of2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2-benzazepin-1-one

(1-Oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl) acetate as a startingmaterial was used in the same manner as in Example 1 to obtained thetitle compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.56 (d, J=8.5 Hz, 1H), 7.15-7.02 (m,4H), 6.97 (dd, J=9.0, 1.9 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 4.32-4.22 (m,1H), 4.14 (dd, J=9.9, 4.1 Hz, 1H), 4.05 (dd, J=9.8, 6.0 Hz, 1H), 3.78(s, 2H), 3.07 (t, J=6.5 Hz, 2H), 2.98-2.86 (m, 4H), 2.86-2.78 (m, 3H),2.73 (dd, J=13.1, 7.5 Hz, 1H), 2.09-1.97 (m, 2H).

Example 4: Synthesis of2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one

6-(Trifluoromethoxy)tetralin-1-one as a starting material was used inthe same manner as in Example 1 to obtained the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.5,2.3 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.10-6.96 (m, 4H), 4.23-4.13 (m,1H), 3.88 (dd, J=13.8, 3.6 Hz, 1H), 3.70 (s, 2H), 3.41-3.29 (m, 2H),3.30-3.20 (m, 1H), 2.92-2.84 (m, 2H), 2.84-2.73 (m, 4H), 2.64-2.52 (m,2H), 2.15-2.04 (m, 2H).

Example 5: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 1,except that 7-(trifluoromethyl)chroman-4-one was used as a startingmaterial and (R)-(−)-glycidyl nosylate was used instead ofepibromohydrin in Example 1-1.

¹H NMR (400 MHz, Methanol-d₄) δ 7.90 (d, J=8.2 Hz, 1H), 7.48 (d, J=8.2Hz, 1H), 7.36 (s, 1H), 7.16-7.03 (m, 4H), 4.56 (t, J=5.1 Hz, 2H),4.25-4.22 (m, 1H), 4.02 (dd, J=13.9, 3.5 Hz, 1H), 3.76-3.74 (s, 4H),3.47 (dd, J=14.0, 8.0 Hz, 1H), 2.99-2.83 (m, 4H), 2.73-2.60 (m, 2H).

Example 6: Synthesis of2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one

7-(Trifluoromethoxy)-2,3,4,5-tetrahydro-2-benzazepin-1-one as a startingmaterial was used in the same manner as in Example 5 to obtained thetitle compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.5 Hz, 1H), 7.27 (d, J=8.6Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.16-7.02 (m, 4H), 4.29-4.20 (m, 1H),3.94 (dd, J=13.8, 3.6 Hz, 1H), 3.78 (s, 2H), 3.48-3.34 (m, 2H), 3.37 (d,J=6.7 Hz, 1H), 2.99-2.82 (m, 6H), 2.72-2.59 (m, 2H), 2.18 (q, J=6.8 Hz,2H).

Example 7: Synthesis of2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-ethoxy-4,5-dihydro-3H-2-benzazepin-1-one

7-Ethoxy-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting materialwas used in the same manner as in Example 5 to obtained the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.52 (d, J=8.5 Hz, 1H), 7.19-7.04 (m,4H), 6.92-6.84 (m, 1H), 6.78 (s, 1H), 4.30-4.20 (m, 1H), 4.09 (q, J=7.1Hz, 2H), 3.91 (dd, J=13.8, 3.8 Hz, 1H), 3.82 (s, 2H), 3.40 (td, J=13.6,12.5, 7.2 Hz, 3H), 3.03-2.90 (m, 4H), 2.79 (t, J=7.1 Hz, 2H), 2.73-2.62(m, 2H), 2.19-2.07 (m, 2H), 1.41 (t, J=7.0 Hz, 3H).

Example 8: Synthesis of[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-yl]trifluoromethanesulfonate

(1-Oxo-2,3,4,5-tetrahydro-2-benzazepin-7-yl) trifluoromethanesulfonateas a starting material was used in the same manner as in Example 5 toobtained the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.74 (d, J=8.2 Hz, 1H), 7.38 (dd, J=8.5,2.4 Hz, 1H), 7.32 (d, J=2.3 Hz, 1H), 7.18-6.99 (m, 4H), 4.30-4.19 (m,1H), 3.94 (dd, J=13.8, 3.6 Hz, 1H), 3.78 (s, 2H), 3.46-3.3.4 (m, 3H),2.98-2.83 (m, 6H), 2.71-2.62 (m, 2H), 2.18 (p, J=6.8 Hz, 2H).

Example 9: Synthesis of2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-carbonitrile

7-Cyano-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material wasused in the same manner as in Example 5 to obtained the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.73 (s, 2H), 7.66 (s, 1H), 7.21-7.02(m, 4H), 4.31-4.17 (m, 1H), 3.94 (dd, J=13.9, 3.6 Hz, 1H), 3.77 (s, 2H),3.57-3.34 (m, 3H), 3.01-2.81 (m, 6H), 2.70-2.61 (t, J=5.4 Hz, 2H), 2.17(p, J=7.0 Hz, 2H).

Example 10: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Example 10-1: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-3,4-dihydro-2H-1,4-benzoxazepin-5-one as a starting material wasused in the same manner as in Example 5 to obtained the title compound.

Example 10-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(96 mg, 0.22 mmol), methylboronic acid (27 mg, 0.45 mmol),Pd(dppf)Cl₂CH₂Cl₂ (18 mg, 0.022 mmol) and potassium carbonate (91 mg,0.66 mg) were dissolved in 10 mL of 1,4-dioxane:distilled water (=3:1)solvent and stirred at 100° C. After confirming that the reaction wascomplete, the reaction solution was concentrated under reduced pressureand filtered with ethyl acetate. The filtrate was concentrated underreduced pressure and purified by flash column chromatography to obtainthe title compound (11 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.59 (d, J=7.9 Hz, 1H), 7.18-6.98 (m,5H), 6.88 (s, 1H), 4.45 (t, J=5.2 Hz, 2H), 4.23 (p, J=3.3 Hz, 1H), 3.98(dd, J=13.9, 3.6 Hz, 1H), 3.76 (s, 2H), 3.69 (t, J=5.3 Hz, 2H), 3.43(dd, J=13.9, 7.7 Hz, 1H), 2.98-2.83 (m, 4H), 2.71-2.59 (m, 2H), 2.36 (s,3H).

Example 11: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propyl-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 10,except that propylboronic acid was used instead of methylboronic acid inExample 10-2. ¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=7.9 Hz, 1H),7.16-6.99 (m, 5H), 6.88 (s, 1H), 4.46 (t, J=5.2 Hz, 2H), 4.25 (dd,J=8.3, 4.3 Hz, 1H), 3.98 (dd, J=13.9, 3.7 Hz, 1H), 3.78 (s, 2H), 3.70(t, J=5.2 Hz, 2H), 3.45 (dd, J=13.9, 7.6 Hz, 1H), 2.97-2.88 (m, 4H),2.73-2.65 (m, 2H), 2.62 (t, J=7.6 Hz, 2H), 1.67 (q, J=7.5 Hz, 2H), 0.97(t, J=7.3 Hz, 3H).

Example 12: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.23 mmol), isobutylboronic acid (47 mg, 0.46 mmol),Pd(dppf)Cl₂ (17 mg, 0.023 mmol) and potassium carbonate (95 mg, 0.69 mg)were dissolved in 2 mL of toluene and stirred at 120° C. for 2 hours.After confirming that the boronic acid reaction was complete, thereaction solution was concentrated under reduced pressure and filteredwith ethyl acetate. The filtrate was concentrated under reduced pressureand purified by flash column chromatography to obtain the title compound(11 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.0 Hz, 1H), 7.16-7.03 (m,4H), 7.00 (dd, J=7.9, 1.6 Hz, 1H), 6.85 (d, J=1.6 Hz, 1H), 4.46 (t,J=5.1 Hz, 2H), 4.28-4.20 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.76(s, 2H), 3.70 (t, J=5.2 Hz, 2H), 3.44 (dd, J=13.9, 7.6 Hz, 1H),2.97-2.84 (m, 4H), 2.69-2.59 (m, 2H), 2.51 (d, J=7.2 Hz, 2H), 1.96-1.83(m, 1H), 0.93 (d, J=6.6 Hz, 6H).

Example 13: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 3,3,3-trifluoropropylboronic acid was used instead ofisobutylboronic acid at 100° C.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.0 Hz, 1H), 7.19-7.05 (m,5H), 6.97 (s, 1H), 4.48 (t, J=5.1 Hz, 2H), 4.28-4.25 (m, 1H), 3.98 (dd,J=13.8, 3.7 Hz, 1H), 3.81 (s, 2H), 3.71 (t, J=5.3 Hz, 2H), 3.46 (dd,J=13.9, 7.6 Hz, 1H), 2.96-2.89 (m, 6H), 2.76-2.64 (m, 2H), 2.59-2.44 (m,2H).

Example 14: Synthesis of tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

The title compound was synthesized in the same manner as in Example 10,except that tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylatewas used instead of methylboronic acid in Example 10-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.3 Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 7.19-7.03 (m, 5H), 6.26 (s, 1H), 4.49 (t, J=5.2 Hz, 2H),4.30-4.19 (m, 1H), 4.16-4.05 (m, 2H), 4.00 (dd, J=13.8, 3.8 Hz, 1H),3.77 (s, 2H), 3.76-3.69 (m, 2H), 3.70-3.60 (m, 2H), 3.45 (dd, J=14.0,7.7 Hz, 1H), 2.98-2.85 (m, 4H), 2.73-2.63 (m, 2H), 2.55 (s, 2H), 1.51(s, 9H).

Example 15: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

Tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylateobtained in Example 14 was dissolved in methanol, and 4 N hydrochloricacid solution dissolved in 1,4-dioxane was added thereto. The mixturewas stirred at room temperature until the reaction was completed,diluted with ethyldiethyl ether, and filtered to obtain the titlecompound in the form of a white solid dihydrochloride. After addition ofwater, the title compound in the form of a dihydrochloride was washedwith ethyl acetate 3 times. The obtained aqueous layer was basified withsodium hydroxide aqueous solution until the pH reached 14, and ethylacetate was added again to extract 3 times. The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to obtain the title compound without additionalpurification.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.3Hz, 1H), 7.17-7.01 (m, 5H), 6.32 (s, 1H), 4.49 (t, J=5.1 Hz, 2H),4.29-4.19 (m, 1H), 4.00 (dd, J=14.0, 3.6 Hz, 1H), 3.79-3.65 (m, 4H),3.53 (d, J=3.2 Hz, 2H), 3.45 (dd, J=13.9, 7.7 Hz, 1H), 3.11 (t, J=5.8Hz, 2H), 2.98-2.84 (m, 4H), 2.71-2.62 (m, 2H), 2.53 (bs, 2H).

Example 16: Synthesis of8-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Dihydrochloride of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 15 (75 mg, 0.16 mmol) and potassium carbonate (66mg, 0.48 mmol) were dissolved in 1.5 mL of acetone, and acetic anhydride(0.03 mLm 0.32 mmol) was slowly added thereto at room temperature. Thereaction solution was stirred at room temperature and filtered afterconfirming that the reaction was complete. The filtrate was concentratedunder reduced pressure and purified by flash column chromatography toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 7.19-7.02 (m, 5H), 6.28 (s, 1H), 4.49 (t, J=5.1 Hz, 2H),4.31-4.19 (m, 3H), 3.98 (dd, J=13.9, 3.7 Hz, 1H), 3.88-3.78 (m, 3H),3.80-3.67 (m, 3H), 3.47 (dd, J=13.9, 7.5 Hz, 1H), 3.02-2.90 (m, 4H),2.77-2.68 (m, 2H), 2.64 (bs, 1H), 2.56 (bs, 1H), 2.18 (d, J=15.1 Hz,3H).

Example 17: Synthesis of8-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 17-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazepin-5-one

Tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylateobtained in Example 14 was dissolved in methanol, and 5%palladium-charcoal in a catalytic amount was added thereto. The reactionsolution was stirred under a hydrogen balloon and filtered throughcelite. The filtrate was concentrated under reduced pressure, dissolvedin a small amount of methanol, and then 4 N hydrochloric acid dissolvedin 1,4-dioxane was added thereto, followed by stirring at roomtemperature for 1 hour. After addition of distilled water, the reactionsolution was washed with ethyl acetate. The obtained aqueous layer wasbasified with sodium hydroxide aqueous solution until the pH reached 14and extracted with dichloromethane 3 times. The combined organic layerswere dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure to obtain the title compound without additionalpurification.

Example 17-2: Synthesis of8-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyl)-2,3-dihydro-1,4-benzoxazepin-5-one(50 mg, 0.11 mmol) obtained in Example 17-1 and potassium carbonate (46mg, 0.33 mg) were dissolved in dichloromethane, and acetic anhydride(0.02 mL, 0.17 mmol) was slowly added thereto. The reaction solution wasstirred at room temperature for one day, diluted with dichloromethane,filtered, and concentrated under reduced pressure. The obtainedconcentrate was purified by flash column chromatography to obtain thetitle compound (21 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (d, J=8.0 Hz, 1H), 7.18-7.02 (m,5H), 6.95 (s, 1H), 4.69 (d, J=13.4 Hz, 1H), 4.47 (t, J=5.2 Hz, 2H),4.29-4.18 (m, 1H), 4.03 (dd, J=27.3, 14.3 Hz, 2H), 3.80-3.65 (m, 4H),3.44 (dd, J=14.0, 7.7 Hz, 1H), 3.29-3.20 (m, 1H), 2.98-2.82 (m, 4H),2.80-2.60 (m, 3H), 2.16 (s, 3H), 1.98-1.85 (m, 2H), 1.78-1.50 (m, 3H).

Example 18: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

Dihydrochloride of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 15 (75 mg, 0.16 mmol) was dissolved in methanol, andan excess of acetaldehyde was added thereto. While stirring the reactionsolution, an excess of sodium cyanoborohydride was added, followed bystirring at room temperature for one day. The reaction was terminated byadding saturated aqueous ammonium chloride solution to the reactionsolution, and 1 N sodium hydroxide aqueous solution was added forbasification. The reaction mixture was extracted with ethyl acetate 3times and dried over anhydrous sodium sulfate. The oily liquid obtainedby removing the solvent by evaporation under reduced pressure waspurified by flash column chromatography to obtain the title compound (10mg) as a white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.2 Hz, 1H), 7.30 (d, J=7.9Hz, 1H), 7.09 (d, J=18.9 Hz, 5H), 6.30 (s, 1H), 4.49 (t, J=5.1 Hz, 2H),4.29-4.18 (m, 1H), 4.00 (dd, J=13.7, 3.5 Hz, 1H), 3.77 (s, 2H), 3.73 (t,J=5.2 Hz, 2H), 3.45 (dd, J=13.8, 7.6 Hz, 1H), 3.27 (s, 2H), 2.99-2.85(m, 4H), 2.83 (t, J=5.9 Hz, 2H), 2.71-2.59 (m, 6H), 1.21 (t, J=7.2 Hz,3H).

Example 19: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 18,except that acetone was used instead of acetaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=8.2 Hz, 1H), 7.23 (d, J=8.2Hz, 1H), 7.10-6.95 (m, 5H), 6.24 (s, 1H), 4.42 (t, J=5.2 Hz, 2H),4.22-4.12 (m, 1H), 3.96-3.84 (m, 1H), 3.71 (s, 2H), 3.65 (t, J=5.2 Hz,2H), 3.48-3.31 (m, 3H), 3.05-2.90 (m, 3H), 2.90-2.78 (m, 4H), 2.68-2.50(m, 4H), 1.17 (d, J=6.5 Hz, 6H).

Example 20: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 10,except that2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanewas used instead of methylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.2 Hz, 1H), 7.30 (d, J=8.3Hz, 1H), 7.20-6.98 (m, 5H), 6.34 (s, 1H), 4.49 (t, J=5.1 Hz, 2H), 4.32(d, J=3.3 Hz, 2H), 4.29-4.19 (m, 1H), 4.00 (dd, J=13.8, 3.6 Hz, 1H),3.94 (t, J=5.5 Hz, 2H), 3.81-3.68 (m, 4H), 3.48-3.40 (m, 1H), 2.99-2.84(m, 4H), 2.69-2.60 (m, 2H), 2.53 (bs, 2H).

Example 21: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yl-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 20 was dissolved in methanol, and 5%palladium-charcoal in a catalytic amount was added thereto. The reactionsolution was stirred under a hydrogen balloon and filtered throughcelite. The filtrate was concentrated under reduced pressure andpurified by flash chromatography to obtain the title compound astransparent oil.

¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (d, J=8.1 Hz, 1H), 7.17-7.02 (m,5H), 6.95 (s, 1H), 4.48 (t, J=5.2 Hz, 2H), 4.29-4.17 (m, 1H), 4.08-3.95(m, 3H), 3.76 (s, 2H), 3.71 (t, J=5.3 Hz, 2H), 3.63-3.52 (m, 2H), 3.44(dd, J=13.9, 7.7 Hz, 1H), 2.98-2.80 (m, 5H), 2.69-2.59 (m, 2H),1.84-1.72 (m, 4H).

Example 22: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(160 mg, 0.37 mmol), potassium (morpholin-4-yl)methyltrifluoroborate (85mg, 0.41 mg), palladium acetate (4 mg, 0.0185 mmol), XPhos (18 mg, 0.037mmol) and cesium carbonate (362 mg, 1.11 mmol) were dissolved in 3 mL oftetrahydrofuran:distilled water (=10:1) solvent, and nitrogen wascharged, followed by stirring at 80° C. for 16 hours. The reactionsolution was cooled to room temperature, diluted with ethyl acetate, andfiltered through celite. The obtained solution was concentrated underreduced pressure and purified by flash chromatography to obtain thewhite title compound (103 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.16-7.03 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.30-4.19 (m, 1H),3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.77 (s, 2H), 3.71 (t, J=4.8 Hz, 6H),3.55 (s, 2H), 3.46 (dd, J=13.9, 7.6 Hz, 1H), 2.99-2.85 (m, 4H),2.72-2.60 (m, 2H), 2.48 (t, J=4.7 Hz, 4H).

Example 23: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 22,except that potassium (piperidin-1-yl)methyltrifluoroborate was usedinstead of potassium (morpholin-4-yl) methyltrifluoroborate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.15-7.02 (m, 5H), 4.49 (t, J=5.1 Hz, 2H), 4.29-4.20 (m, 1H),4.00 (dd, J=13.8, 3.6 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J=5.3 Hz, 2H),3.53 (s, 2H), 3.45 (dd, J=13.8, 7.6 Hz, 1H), 2.96-2.86 (m, 4H),2.71-2.59 (m, 2H), 2.46 (bs, 4H), 1.62 (q, J=5.6 Hz, 4H), 1.49 (bs, 2H).

Example 24: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 22,except that potassium 1-trifluoroboratomethylpyrrolidine was usedinstead of potassium (morpholin-4-yl) methyltrifluoroborate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.15-7.03 (m, 5H), 4.49 (t, J=5.1 Hz, 2H), 4.27-4.24 (m, 1H),4.00 (dd, J=13.9, 3.6 Hz, 1H), 3.81-3.67 (m, 6H), 3.46 (dd, J=13.9, 7.7Hz, 1H), 2.95-2.88 (m, 4H), 2.66 (bs, 6H), 1.87 (bs, 4H).

Example 25: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 22,except that potassium dimethylaminomethyltrifluoroboronate was usedinstead of potassium (morpholin-4-yl) methyltrifluoroborate.

¹H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J=8.0 Hz, 1H), 7.18-7.07 (m,4H), 7.06-6.95 (m, 2H), 4.51-4.39 (m, 2H), 4.17-4.06 (m, 2H), 3.93 (d,J=14.7 Hz, 1H), 3.83 (d, J=15.0 Hz, 1H), 3.74-3.66 (m, 2H), 3.63 (d,J=14.9 Hz, 1H), 3.56 (dd, J=14.2, 6.0 Hz, 1H), 3.42 (s, 2H), 3.00-2.87(m, 3H), 2.77-2.70 (m, 1H), 2.69-2.63 (m, 1H), 2.56 (t, J=11.3 Hz, 1H),2.25 (s, 6H).

Example 26: Synthesis of8-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 22,except that potassium diethylaminomethyltrifluoroboronate was usedinstead of potassium (morpholin-4-yl) methyltrifluoroborate.

¹H NMR (400 MHz, Chloroform-d) δ 7.74 (d, J=7.9 Hz, 1H), 7.18-7.08 (m,4H), 7.02 (bs, 2H), 4.45 (qt, J=10.8, 4.6 Hz, 2H), 4.16-4.06 (m, 1H),3.93 (d, J=14.2 Hz, 1H), 3.83 (d, J=14.9 Hz, 1H), 3.75-3.66 (m, 2H),3.63 (d, J=14.9 Hz, 1H), 3.57-3.54 (m, 3H), 3.00-2.87 (m, 3H), 2.74 (dd,J=10.7, 5.3 Hz, 1H), 2.67 (dd, J=12.5, 3.9 Hz, 1H), 2.61-2.47 (m, 5H),1.04 (t, J=7.1 Hz, 6H).

Example 27: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-Methyl piperidine (0.054 mL, 0.46 mmol) and potassium(bromomethyl)trifluoroborate (92 mg, 0.46 mmol) were dissolved in 2 mLof tetrahydrofuran, and stirred at 80° C. for 12 hours. The reactionmixture was cooled to room temperature, and8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.23 mmol), palladium acetate (3 mg, 0.011 mmol), XPhos (11 mg,0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) and 2 mL oftetrahydrofuran:distilled water (=10:1) were added thereto, followed bycharging a reaction vessel with nitrogen. The reaction solution wasstirred at 80° C. for 16 hours, diluted with ethyl acetate, and filteredthrough celite. The obtained solution was concentrated under reducedpressure and purified by flash chromatography to obtain the white titlecompound (70 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.14-7.02 (m, 5H), 4.49 (t, J=5.1 Hz, 2H), 4.29-4.19 (m, 1H),4.00 (dd, J=13.9, 3.6 Hz, 1H), 3.76 (s, 2H), 3.72 (t, J=5.2 Hz, 2H),3.54 (s, 2H), 3.46 (dd, J=13.8, 7.7 Hz, 1H), 2.98-2.83 (m, 6H),2.72-2.60 (m, 2H), 2.07 (d, J=11.6 Hz, 1H), 1.66 (d, J=13.0 Hz, 2H),1.41 (bs, 1H), 1.34-1.19 (m, 2H), 0.96 (d, J=6.4 Hz, 3H).

Example 28: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 27,except that 4 equivalents of potassium carbonate was added, and2-oxa-6-azaspiro[3.3]heptane oxalate was used instead of 4-methylpiperidine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18-7.03 (m,5H), 6.98 (s, 1H), 4.75 (s, 4H), 4.48 (t, J=5.1 Hz, 2H), 4.30-4.19 (m,1H), 3.99 (dd, J=14.0, 3.6 Hz, 1H), 3.78 (s, 2H), 3.71 (t, J=5.3 Hz,2H), 3.62 (s, 2H), 3.47-3.43 (m, 5H), 2.95-2.89 (m, 4H), 2.74-2.61 (m,2H).

Example 29: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

3-Methoxyazetidine hydrochloride (57 mg, 0.46 mmol), potassium(bromomethyl)trifluoroborate (92 mg, 0.46 mmol) and potassium carbonate(127 mg, 0.92 mmol) were dissolved in tetrahydrofuran:distilled water(10:1), and stirred at 80° C. for 12 hours. The reaction mixture wascooled to room temperature, and8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.23 mmol), palladium acetate (3 mg, 0.011 mmol), XPhos (11 mg,0.023 mmol), cesium carbonate (225 mg, 0.69 mmol) andtetrahydrofuran:distilled water (=10:1) were added thereto, followed bycharging a reaction vessel with nitrogen. The reaction solution wasstirred at 80° C. for 16 hours, diluted with ethyl acetate, and filteredthrough celite. The obtained solution was concentrated under reducedpressure and purified by flash chromatography to obtain the white titlecompound (16 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.16-7.04 (m,5H), 7.00 (s, 1H), 4.48 (t, J=5.1 Hz, 2H), 4.28-4.19 (m, 1H), 4.11-4.04(m, 1H), 3.99 (dd, J=13.9, 3.7 Hz, 1H), 3.77 (s, 2H), 3.74-3.67 (m, 3H),3.61 (t, J=7.3 Hz, 2H), 3.45 (dd, J=14.0, 7.6 Hz, 1H), 3.27 (s, 3H),3.08 (t, J=7.1 Hz, 2H), 3.00-2.84 (m, 4H), 2.71-2.61 (m, 2H).

Example 30: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-methylmorpholin-4-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 2-methylmorpholine was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.15-7.03 (m, 5H), 4.49 (t, J=5.1 Hz, 2H), 4.30-4.17 (m, 1H),3.99 (dd, J=13.8, 3.7 Hz, 1H), 3.88-3.79 (m, 1H), 3.77 (s, 2H),3.75-3.61 (m, 4H), 3.54 (s, 2H), 3.46 (dd, J=13.8, 7.6 Hz, 1H),2.98-2.84 (m, 4H), 2.76 (d, J=11.4 Hz, 1H), 2.72-2.62 (m, 3H), 2.21-2.11(m, 1H), 1.86 (t, J=10.6 Hz, 1H), 1.12 (d, J=6.3 Hz, 3H).

Example 31: Synthesis of8-[(4,4-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 4,4-difluoropiperidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.15-7.03 (m, 4H), 4.49 (t, J=5.1 Hz, 2H), 4.29-4.19 (m, 1H),4.00 (dd, J=13.8, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J=5.2 Hz, 2H),3.60 (s, 2H), 3.46 (dd, J=13.8, 7.6 Hz, 1H), 2.99-2.84 (m, 4H),2.71-2.64 (m, 2H), 2.59 (t, J=5.8 Hz, 4H), 2.01 (ddt, J=19.4, 12.4, 5.6Hz, 4H).

Example 32: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 4-fluoropiperidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.14-7.01 (m, 5H), 4.67 (d, J=48.8 Hz, 1H), 4.48 (t, J=5.1 Hz,2H), 4.29-4.17 (m, 1H), 3.99 (dd, J=13.8, 3.6 Hz, 1H), 3.81-3.67 (m,4H), 3.55 (s, 2H), 3.45 (dd, J=13.9, 7.7 Hz, 1H), 2.99-2.83 (m, 4H),2.72-2.54 (m, 4H), 2.50-2.35 (m, 2H), 2.00-1.76 (m, 4H).

Example 33: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3,5-dimethyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3,5-dimethylpiperidine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.16-6.95 (m, 4H), 4.49 (t, J=5.2 Hz, 2H), 4.25 (s, 1H), 4.00(dd, J=14.0, 3.6 Hz, 1H), 3.75 (d, J=16.5 Hz, 2H), 3.55 (s, 2H), 3.46(dd, J=13.7, 7.7 Hz, 1H), 3.01-2.81 (m, 5H), 2.67 (d, J=5.2 Hz, 2H),1.75 (d, J=13.2 Hz, 3H), 1.55 (t, J=11.0 Hz, 2H), 0.87 (d, J=6.3 Hz,6H).

Example 34: Synthesis of8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-ylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrolehydrochloride was used instead of 3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (s, OH),7.14-7.02 (m, 4H), 4.48 (t, J=5.1 Hz, 2H), 4.24 (s, 1H), 4.00 (dd,J=13.9, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.60 (s, 2H),3.46 (dt, J=13.8, 7.6 Hz, 1H), 2.94 (d, J=5.5 Hz, 2H), 2.89 (d, J=6.2Hz, 3H), 2.76-2.59 (m, 4H), 2.08 (dd, J=9.4, 5.4 Hz, 2H), 1.62 (d,J=41.3 Hz, 4H), 1.47 (s, 2H).

Example 35: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxypyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that pyrrolidin-3-ol was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.12 (d, J=4.2 Hz, 3H), 7.08 (s, 2H), 4.48 (t, J=5.2 Hz, 2H),4.37 (s, 1H), 4.24 (s, 1H), 4.00 (dd, J=13.7, 3.6 Hz, 1H), 3.77 (s, 2H),3.75-3.68 (m, 3H), 3.65 (d, J=13.0 Hz, 1H), 3.46 (dt, J=13.8, 7.4 Hz,1H), 2.94 (d, J=5.6 Hz, 2H), 2.89 (d, J=5.4 Hz, 2H), 2.84-2.74 (m, 2H),2.75-2.63 (m, 2H), 2.61-2.48 (m, 2H), 2.16 (dt, J=14.3, 7.0 Hz, 1H).

Example 36: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that (2R)-2-methylpyrrolidine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.12 (d, J=4.3 Hz, 3H), 7.07 (s, 2H), 4.49 (t, J=5.2 Hz, 2H),4.24 (s, OH), 4.11-3.93 (m, 2H), 3.76 (s, 2H), 3.72 (t, J=5.3 Hz, 2H),3.46 (dt, J=13.9, 7.7 Hz, 1H), 3.24 (d, J=12.9 Hz, 1H), 2.94 (d, J=5.7Hz, 3H), 2.89 (d, J=5.7 Hz, 2H), 2.71-2.62 (m, 2H), 2.57-2.45 (m, 1H),2.24 (d, J=9.2 Hz, 1H), 2.03 (dq, J=14.6, 7.3 Hz, 1H), 1.74 (p, J=8.1Hz, 2H), 1.49 (dt, J=17.6, 8.9 Hz, 1H), 1.21 (d, J=6.1 Hz, 3H).

Example 37: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3-piperidylmethanol was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.12 (d, J=4.2 Hz, 3H), 7.06 (s, 2H), 4.49 (t, J=5.1 Hz, 2H),4.24 (s, 1H), 3.99 (dd, J=14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t,J=5.0 Hz, 2H), 3.65-3.53 (m, 2H), 3.54-3.41 (m, 1H), 3.00 (d, J=7.1 Hz,1H), 2.94 (d, J=5.4 Hz, 2H), 2.88 (t, J=10.9 Hz, 3H), 2.73-2.61 (m, 2H),2.16-1.95 (m, 1H), 1.76 (d, J=18.7 Hz, 2H), 1.63 (d, J=12.4 Hz, 1H).

Example 38: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methoxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 4-methoxypiperidine was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0Hz, 1H), 7.15-7.01 (m, 5H), 4.49 (t, J=5.2 Hz, 2H), 4.31-4.19 (m, 1H),4.00 (dd, J=13.8, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J=4.8 Hz, 2H),3.55 (s, 2H), 3.46 (dd, J=13.8, 7.7 Hz, 1H), 3.34 (s, 3H), 3.31-3.24 (m,1H), 2.98-2.85 (m, 4H), 2.76 (dd, J=11.1, 3.9 Hz, 2H), 2.71-2.62 (m,2H), 2.25 (t, J=10.8 Hz, 2H), 1.99-1.87 (m, 2H), 1.67-1.52 (m, 2H).

Example 39: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 1,4-oxazepane hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.15-7.03 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.29-4.19 (m, 1H),3.99 (dd, J=13.7, 3.6 Hz, 1H), 3.83 (t, J=6.1 Hz, 2H), 3.79-3.65 (m,8H), 3.46 (dd, J=13.8, 7.6 Hz, 1H), 2.98-2.84 (m, 4H), 2.78-2.68 (m,4H), 2.69-2.61 (m, 2H), 1.93 (p, J=5.8 Hz, 2H).

Example 40: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-3-methyl-pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3-methylpyrrolidin-3-ol was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.16-7.01 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.30-4.19 (m, 1H),4.00 (dd, J=14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.75-3.61 (m, 4H), 3.46(dd, J=13.9, 7.6 Hz, 1H), 2.94 (d, J=5.6 Hz, 2H), 2.92-2.80 (m, 4H),2.73-2.60 (m, 4H), 2.55 (d, J=10.1 Hz, 1H), 1.95-1.85 (m, 2H), 1.36 (s,3H).

Example 41: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[2-(hydroxymethyl)-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that morpholin-3-ylmethanol was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 7.15-7.04 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.29-4.19 (m, 1H),4.14 (d, J=13.3 Hz, 1H), 3.99 (dd, J=14.0, 3.5 Hz, 1H), 3.91-3.84 (m,1H), 3.83-3.75 (m, 3H), 3.75-3.63 (m, 4H), 3.64-3.50 (m, 2H), 3.46 (dd,J=13.8, 7.6 Hz, 1H), 3.39 (d, J=13.9 Hz, 1H), 2.99-2.85 (m, 4H),2.72-2.63 (m, 3H), 2.53 (s, 1H), 2.29 (d, J=9.3 Hz, 1H).

Example 42: Synthesis of8-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3,3-difluoropiperidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.09 (dd, J=21.4, 4.6 Hz, 4H), 4.49 (t, J=5.2 Hz, 2H),4.31-4.20 (m, 1H), 3.99 (dd, J=14.0, 3.6 Hz, 1H), 3.78 (s, 2H), 3.72 (t,J=5.3 Hz, 2H), 3.63 (s, 2H), 3.46 (dd, J=13.9, 7.9 Hz, 1H), 3.00-2.83(m, 4H), 2.74-2.58 (m, 4H), 2.55-2.44 (m, 2H), 1.97-1.83 (m, 2H),1.82-1.72 (m, 2H).

Example 43: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3-fluoropiperidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.15-7.02 (m, 5H), 4.63 (d, J=48.0 Hz, 1H), 4.49 (t, J=5.1 Hz,2H), 4.30-4.19 (m, 1H), 4.00 (dd, J=14.0, 3.6 Hz, 1H), 3.77 (s, 2H),3.72 (t, J=5.3 Hz, 2H), 3.58 (s, 2H), 3.46 (dd, J=13.9, 7.7 Hz, 1H),3.00-2.82 (m, 4H), 2.81-2.58 (m, 3H), 2.55-2.41 (m, 2H), 2.38 (t, J=9.9Hz, 1H), 1.94-1.78 (m, 2H), 1.70-1.51 (m, 2H).

Example 44: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that piperidin-3-ol hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.16-7.01 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.30-4.19 (m, 1H),3.99 (dd, J=13.7, 3.6 Hz, 1H), 3.78 (s, 2H), 3.75-3.63 (m, 3H),3.63-3.50 (m, 2H), 3.46 (dd, J=13.9, 7.7 Hz, 1H), 3.00-2.82 (m, 5H),2.77-2.61 (m, 3H), 2.12-2.04 (m, 1H), 1.99-1.88 (m, 2H), 1.82-1.70 (m,1H), 1.65-1.50 (m, 1H).

Example 45: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that piperidin-4-ol was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.15-7.03 (m, 5H), 4.49 (t, J=5.0 Hz, 2H), 4.29-4.20 (m, 1H),4.02-3.96 (m, 1H), 3.77 (s, 2H), 3.76-3.70 (m, 2H), 3.68-3.59 (m, 1H),3.55 (s, 2H), 3.46 (dd, J=13.8, 7.5 Hz, 1H), 2.98-2.86 (m, 4H),2.86-2.76 (m, 2H), 2.70-2.63 (m, 2H), 2.28-2.15 (m, 2H), 1.92-1.82 (m,2H), 1.66-1.53 (m, 2H).

Example 46: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that [(2S)-pyrrolidin-2-yl]methanol was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.16-7.03 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.29-4.19 (m, 1H),4.13 (d, J=12.8 Hz, 1H), 4.00 (dd, J=14.1, 3.6 Hz, 1H), 3.77 (s, 2H),3.72 (t, J=5.4 Hz, 2H), 3.60 (dd, J=11.1, 4.6 Hz, 1H), 3.56-3.41 (m,3H), 3.02-2.85 (m, 5H), 2.79-2.62 (m, 3H), 2.39-2.25 (m, 1H), 2.03-1.93(m, 1H), 1.82-1.66 (m, 3H).

Example 47: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that [(2R)-pyrrolidin-2-yl]methanol was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.17-7.02 (m, 5H), 4.48 (t, J=5.2 Hz, 2H), 4.24 (s, 1H), 4.14(d, J=13.2 Hz, 1H), 3.99 (dd, J=13.8, 3.5 Hz, 1H), 3.77 (s, 2H), 3.72(t, J=4.9 Hz, 2H), 3.60 (dd, J=11.0, 4.6 Hz, 1H), 3.57-3.41 (m, 3H),3.02-2.84 (m, 5H), 2.79-2.68 (m, 1H), 2.69-2.61 (m, 2H), 2.38-2.27 (m,1H), 2.05-1.92 (m, 1H), 1.83-1.66 (m, 3H).

Example 48: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethylpyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 2-ethylpyrrolidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.16-7.02 (m, 5H), 4.48 (t, J=5.2 Hz, 2H), 4.29-4.19 (m, 1H),4.07 (d, J=13.2 Hz, 1H), 4.00 (dd, J=14.1, 3.5 Hz, 1H), 3.76 (s, 2H),3.74-3.67 (m, 2H), 3.45 (dd, J=13.9, 7.7 Hz, 1H), 3.25 (d, J=12.9 Hz,1H), 2.99-2.81 (m, 5H), 2.70-2.60 (m, 2H), 2.41-2.29 (m, 1H), 2.27-2.15(m, 1H), 2.09-1.99 (m, 1H), 1.91-1.80 (m, 1H), 1.79-1.65 (m, 2H),1.57-1.45 (m, 1H), 1.43-1.26 (m, 2H), 0.96 (t, J=7.5 Hz, 3H).

Example 49: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that (2S)-2-(methoxymethyl)pyrrolidine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.16-7.03 (m, 5H), 4.48 (t, J=5.3 Hz, 2H), 4.24 (dd, J=9.6, 5.5Hz, 1H), 4.16 (d, J=13.1 Hz, 1H), 4.00 (d, J=11.2 Hz, 1H), 3.77 (s, 2H),3.72 (t, J=6.2 Hz, 2H), 3.52-3.42 (m, 3H), 3.43-3.36 (m, 1H), 3.36 (s,3H), 2.99-2.85 (m, 5H), 2.84-2.74 (m, 1H), 2.71-2.60 (m, 2H), 2.35-2.24(m, 1H), 2.02-1.88 (m, 1H), 1.80-1.69 (m, 2H), 1.67-1.57 (m, 1H).

Example 50: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that (2R)-2-(methoxymethyl)pyrrolidine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=7.9 Hz, 1H), 7.19 (d, J=7.9Hz, 1H), 7.15-7.02 (m, 5H), 4.48 (t, J=5.2 Hz, 2H), 4.30-4.19 (m, 1H),4.15 (d, J=13.4 Hz, 1H), 4.00 (dd, J=13.9, 3.5 Hz, 1H), 3.76 (s, 2H),3.72 (t, J=5.2 Hz, 2H), 3.51-3.41 (m, 3H), 3.41-3.37 (m, 1H), 3.36 (s,3H), 2.98-2.84 (m, 5H), 2.83-2.74 (m, 1H), 2.71-2.60 (m, 2H), 2.35-2.22(m, 1H), 2.02-1.89 (m, 1H), 1.80-1.68 (m, 2H), 1.68-1.54 (m, 1H).

Example 51: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoropyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3-fluoropyrrolidine hydrochloride was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.16-7.04 (m, 5H), 5.30-5.22 (m, 1H), 5.16-5.08 (m, 1H), 4.49(t, J=5.2 Hz, 2H), 4.30-4.19 (m, 1H), 4.00 (dd, J=13.7, 3.6 Hz, 1H),3.77 (s, 2H), 3.74-3.62 (m, 4H), 3.46 (dd, J=13.9, 7.7 Hz, 1H),2.98-2.89 (m, 4H), 2.71-2.62 (m, 2H), 2.47 (q, J=8.0 Hz, 1H), 2.32-2.13(m, 2H), 2.10-1.91 (m, 2H).

Example 52: Synthesis of8-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 3,3-difluoropyrrolidine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.19 (d, J=8.0Hz, 1H), 7.15-7.02 (m, 5H), 4.49 (t, J=5.0 Hz, 2H), 4.29-4.19 (m, 1H),4.00 (dd, J=14.0, 3.6 Hz, 1H), 3.77 (s, 2H), 3.72 (t, J=4.9 Hz, 2H),3.68 (s, 2H), 3.46 (dd, J=14.0, 7.7 Hz, 1H), 3.00-2.91 (m, 3H),2.92-2.85 (m, 3H), 2.79 (t, J=7.0 Hz, 2H), 2.71-2.62 (m, 2H), 2.36-2.23(m, 2H).

Example 53: Synthesis of 8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 1-piperazin-1-yl-ethanone was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.20 (d, J=8.0Hz, 1H), 7.13 (d, J=4.4 Hz, 3H), 7.07 (s, 2H), 4.49 (t, J=5.1 Hz, 2H),4.25 (s, 1H), 3.99 (dd, J=13.9, 3.7 Hz, 1H), 3.79 (s, 2H), 3.72 (t,J=5.3 Hz, 2H), 3.59 (dq, J=10.4, 5.0 Hz, 7H), 3.47 (dd, J=13.9, 7.6 Hz,1H), 2.93 (dd, J=14.0, 4.7 Hz, 4H), 2.74-2.63 (m, 2H), 2.48 (dt, J=19.1,5.1 Hz, 5H), 2.11 (s, 3H).

Example 54: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 54-1: Synthesis of tert-butyl

4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]methyl]piperazin-1-carboxylate

The title compound was synthesized in the same manner as in Example 29,except that tert-butyl piperazin-1-carboxylate was used instead of3-methoxyazetidine hydrochloride.

Example 54-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperazin-1-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

Tert-butyl4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]methyl]piperazin-1-carboxylateobtained in Example 54-1 was dissolved in methanol, and 4 M hydrochloricacid solution dissolved in 1,4-dioxane was slowly added thereto. Thereaction solution was stirred at room temperature, diluted with diethylether, and filtered to obtain the title compound as a white solid.

Example 54-3: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The obtained hydrochloride was dissolved in methanol, and an excess ofparaformaldehyde and sodium cyanoborohydride were added thereto,followed by stirring at room temperature for 12 hours. The reaction wasterminated by adding a saturated aqueous ammonium chloride solution tothe reaction solution, and 1 N sodium hydroxide aqueous solution wasadded for basification. The mixture was extracted with ethyl acetate 3times and dried over anhydrous sodium sulfate. The pale yellow oilyliquid obtained by removing the solvent by evaporation under reducedpressure was purified by flash chromatography to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.9 Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 7.09 (dd, J=23.3, 5.1 Hz, 5H), 4.48 (t, J=5.3 Hz, 2H),4.28-4.19 (m, 1H), 4.00 (d, J=13.6 Hz, 1H), 3.79-3.67 (m, 4H), 3.56 (s,2H), 3.45 (dd, J=13.8, 7.6 Hz, 1H), 2.98-2.84 (m, 4H), 2.66 (d, J=6.5Hz, 2H), 2.53 (bs, 6H), 2.31 (s, 3H).

Example 55: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride was usedinstead of 3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.16-7.02 (m, 5H), 4.47 (dd, J=11.9, 6.9 Hz, 3H), 4.29-4.19 (m,2H), 4.11 (d, J=7.8 Hz, 1H), 3.99 (dd, J=14.0, 3.6 Hz, 1H), 3.81 (d,J=6.1 Hz, 2H), 3.77 (s, 2H), 3.72 (t, J=5.3 Hz, 2H), 3.65 (d, J=7.9 Hz,1H), 3.54 (s, 1H), 3.46 (dd, J=13.9, 7.6 Hz, 1H), 2.98-2.83 (m, 5H),2.73-2.59 (m, 3H), 2.00-1.93 (m, 1H), 1.76 (d, J=10.2 Hz, 1H).

Example 56: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

Example 56-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(9.0 g, 21 mmol), hydroxypotassium (4.68 g, 83 mmol), Pd(dba)₂ (180 mg,0.315 mmol) and tBuXPhos (270 mg, 0.63 mmol) were dissolved in 80 mL of1,4-dioxane:distilled water (=1:1) solution, and a reaction vessel wascharged with nitrogen. The reaction solution was stirred at 100° C. for3 hours, and a hydrochloric acid aqueous solution was added under an icebath to acidify the reaction solution to pH ˜1. The aqueous layer waswashed with ethyl acetate 3 times, and sodium hydroxide aqueous solutionwas added under an ice bath to basify to pH 14, followed by extractionwith ethyl acetate 3 times. The combined organic layers were dried overanhydrous magnesium sulfate and concentrated under reduced pressure toobtain the title compound as a white solid without additionalpurification.

Example 56-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.27 mmol) obtained in Example 56-1 was dissolved indimethylformamide, and 60% sodium hydride (33 mg, 0.81 mmol) and3-(chloromethyl)pyridine hydrochloride (66 mg, 0.41 mmol) were addedthereto at room temperature. The reaction solution was stirred at roomtemperature for 3 hours and extracted by adding ethyl acetate anddistilled water. The oily liquid obtained by drying the organic layerover anhydrous sodium sulfate and concentrated under reduced pressurewas purified by flash chromatography to obtain the title compound (64mg) as a sticky white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.66 (s, 1H), 8.54 (d, J=4.9 Hz, 1H),7.98 (d, J=8.0 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.50 (t, J=6.6 Hz, 1H),7.18-7.02 (m, 4H), 6.86 (d, J=8.8 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 5.22(s, 2H), 4.49 (t, J=5.0 Hz, 2H), 4.29-4.17 (m, 1H), 3.98 (dd, J=13.8,3.2 Hz, 1H), 3.83-3.67 (m, 4H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 2.99-2.83(m, 4H), 2.71-2.59 (m, 2H).

Example 57: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that 4-(chloromethyl)pyridine hydrochloride was used instead of3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.60-8.51 (m, 2H), 7.71 (d, J=8.8 Hz,1H), 7.54 (d, J=5.2 Hz, 2H), 7.18-7.00 (m, 4H), 6.86 (d, J=9.0 Hz, 1H),6.68 (d, J=2.4 Hz, 1H), 5.25 (s, 2H), 4.48 (t, J=4.9 Hz, 2H), 4.27-4.18(m, 1H), 3.98 (dd, J=14.0, 3.6 Hz, 1H), 3.81-3.67 (m, 4H), 3.43 (dd,J=13.9, 7.7 Hz, 1H), 2.99-2.83 (m, 4H), 2.71-2.60 (m, 2H).

Example 58: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that (2-fluoro-4-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.22 (d, J=5.3 Hz, 1H), 7.71 (dd, J=8.8,2.0 Hz, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.18 (s, 1H), 7.12 (t, J=2.6 Hz,3H), 7.06 (d, J=6.8 Hz, 1H), 6.87 (dd, J=8.9, 2.4 Hz, 1H), 6.69 (d,J=2.5 Hz, 1H), 5.27 (s, 2H), 4.49 (t, J=5.1 Hz, 2H), 4.24 (s, 1H), 3.97(dd, J=13.7, 3.3 Hz, 1H), 3.79 (s, 2H), 3.74 (t, J=4.7 Hz, 2H), 3.44(dd, J=13.9, 7.7 Hz, 1H), 2.93 (dd, J=11.6, 4.7 Hz, 4H), 2.68 (d, J=6.4Hz, 2H).

Example 59: Synthesis of8-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that 2,6-dichloro-4-ethyl-pyridine hydrochloride was used insteadof 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.72 (d, J=8.8 Hz, 1H), 7.53 (s, 2H),7.23-7.06 (m, 2H), 7.06 (s, 1H), 6.86 (d, J=8.7 Hz, 1H), 6.69 (d, J=3.1Hz, 1H), 5.23 (s, 2H), 4.64 (s, 2H), 4.50 (d, J=5.6 Hz, 2H), 4.23 (s,1H), 4.00 (s, 1H), 3.75 (s, 4H), 3.55-3.37 (m, 1H), 2.93 (d, J=5.7 Hz,2H), 2.88 (d, J=5.5 Hz, 2H), 2.64 (d, J=6.2 Hz, 2H).

Example 60: Synthesis of8-[(2,3-difluoro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that (2,3-difluoro-4-pyridyl)methyl methanesulfonate was usedinstead of 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.02 (d, J=5.0 Hz, 1H), 7.83-7.66 (m,1H), 7.51 (d, J=5.3 Hz, 1H), 7.26-7.06 (m, 3H), 7.06 (d, J=6.5 Hz, 1H),6.89-6.84 (m, 1H), 6.71 (d, J=2.9 Hz, 1H), 5.34 (s, 2H), 4.48 (d, J=5.4Hz, 2H), 4.23 (d, J=7.0 Hz, 1H), 4.05-3.92 (m, 1H), 3.75 (d, J=10.7 Hz,4H), 3.43 (dd, J=14.0, 7.7 Hz, 1H), 2.98-2.92 (m, 2H), 2.89 (d, J=5.3Hz, 2H), 2.66 (d, J=6.1 Hz, 2H).

Example 61: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-fluoro-3-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that (6-fluoro-3-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.32 (s, 1H), 8.07 (t, J=8.3 Hz, 1H),7.70 (dd, J=8.8, 2.2 Hz, 1H), 7.20-7.03 (m, 5H), 6.85 (d, J=8.9 Hz, 1H),6.69 (d, J=2.7 Hz, 1H), 5.18 (s, 2H), 4.48 (t, J=5.3 Hz, 2H), 4.23 (s,1H), 3.98 (d, J=13.9 Hz, 1H), 3.75 (d, J=15.5 Hz, 4H), 3.43 (dd, J=14.0,7.8 Hz, 1H), 3.03-2.82 (m, 4H), 2.66 (d, J=6.1 Hz, 2H).

Example 62: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that (3-fluoro-4-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (s, 1H), 8.44 (d, J=5.0 Hz, 1H),7.72 (d, J=8.8 Hz, 1H), 7.65 (t, J=5.7 Hz, 1H), 7.16-7.02 (m, 4H), 6.87(d, J=9.3 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 5.32 (s, 2H), 4.49 (t, J=5.0Hz, 2H), 4.27-4.18 (m, 1H), 3.98 (dd, J=13.7, 3.1 Hz, 1H), 3.79-3.67 (m,4H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 2.97-2.83 (m, 4H), 2.69-2.59 (m,2H).

Example 63: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 56,except that (5-fluoro-2-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride in Example 56-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.49 (s, 1H), 7.68 (dd, J=15.0, 6.3 Hz,3H), 7.16-7.03 (m, 4H), 6.85 (d, J=8.9 Hz, 1H), 6.67 (s, 1H), 5.22 (s,2H), 4.48 (t, J=5.0 Hz, 2H), 4.28-4.16 (m, 1H), 3.98 (d, J=15.0 Hz, 1H),3.78-3.69 (m, 4H), 3.43 (dd, J=13.9, 7.7 Hz, 1H), 3.00-2.83 (m, 4H),2.70-2.61 (m, 2H).

Example 64: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yloxy-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.27 mmol) obtained in Example 56-1, potassium carbonate (112mg, 0.81 mmol) and 4-chlorotetrahydropyran (0.12 mL, 0.81 mmol) weredissolved in dimethylformamide, and stirred at 150° C. for 12 hours orlonger. The reaction solution was cooled to room temperature, anddistilled water was added thereto, followed by extraction with ethylacetate 3 times. The oily liquid obtained by drying the combined organiclayers over anhydrous sodium sulfate and concentrated under reducedpressure was purified by flash chromatography to obtain the titlecompound as a sticky white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.17-7.02 (m,4H), 6.78 (d, J=8.9 Hz, 1H), 6.61 (s, 1H), 4.69-4.61 (m, 1H), 4.48 (t,J=5.0 Hz, 2H), 4.27-4.19 (m, 1H), 4.02-3.91 (m, 3H), 3.78 (s, 2H),3.77-3.70 (m, 2H), 3.62 (t, J=10.0 Hz, 2H), 3.43 (dd, J=13.5, 7.5 Hz,1H), 2.99-2.82 (m, 4H), 2.72-2.60 (m, 2H), 2.11-2.01 (m, 2H), 1.79-1.67(m, 2H).

Example 65: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydropyran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that tetrahydropyran-2-ylmethyl methanesulfonate was used insteadof 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (d, J=8.7 Hz, 1H), 7.12 (d, J=4.1Hz, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.73 (d, J=8.9 Hz, 1H), 6.55 (s, 1H),4.47 (t, J=5.1 Hz, 2H), 4.23 (s, 1H), 4.05-3.94 (m, 1H), 3.89-3.67 (m,7\6H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 2.92 (dd, J=17.2, 5.3 Hz, 4H),2.66 (d, J=6.2 Hz, 2H), 1.89 (d, J=13.1 Hz, 2H), 1.84-1.66 (m, 4H),1.49-1.19 (m, 4H), 1.11 (q, J=12.1 Hz, 2H).

Example 66: Synthesis of8-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that cyclohexylmethyl methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.13 (d, J=5.0Hz, 4H), 7.06 (d, J=6.8 Hz, 1H), 6.76 (d, J=8.9 Hz, 1H), 6.59 (s, 1H),4.46 (d, J=5.2 Hz, 2H), 4.28-4.17 (m, 1H), 3.99 (dd, J=14.1, 9.2 Hz,4H), 3.88-3.66 (m, 6H), 3.53 (td, J=10.8, 3.5 Hz, 1H), 3.43 (dd, J=14.0,7.6 Hz, 1H), 2.94 (dd, J=9.6, 4.6 Hz, 4H), 2.74-2.57 (m, 2H), 1.92 (d,J=6.5 Hz, 1H), 1.69 (t, J=14.9 Hz, 1H), 1.61 (d, J=10.2 Hz, 3H),1.51-1.41 (m, 1H).

Example 67: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that tetrahydrofuran-2-ylmethyl methanesulfonate was used insteadof 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.7 Hz, 1H), 7.20-7.10 (m,3H), 7.04 (d, J=6.7 Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 6.55 (s, 1H), 4.46(q, J=5.4 Hz, 2H), 4.30 (t, J=6.2 Hz, 1H), 4.13 (d, J=8.1 Hz, 1H),4.06-3.90 (m, 4H), 3.86 (dd, J=15.1, 8.3 Hz, 2H), 3.77-3.60 (m, 3H),3.53 (dd, J=14.1, 6.2 Hz, 1H), 3.02-2.87 (m, 4H), 2.84-2.51 (m, 3H),2.31-2.05 (m, 1H), 1.98 (q, J=6.9 Hz, 2H), 1.79 (dt, J=12.0, 7.2 Hz,1H), 1.35-1.22 (m, 1H).

Example 68: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (1-methyl-3-piperidyl) methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (dd, J=8.8, 1.9 Hz, 1H), 7.12 (d,J=2.9 Hz, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 6.61 (d,J=2.9 Hz, 1H), 4.69-4.42 (m, 3H), 4.24 (s, 1H), 3.97 (dd, J=14.5, 3.4Hz, 1H), 3.78 (s, 2H), 3.74 (d, J=5.5 Hz, 2H), 3.43 (dd, J=14.0, 7.6 Hz,1H), 3.03-2.84 (m, 5H), 2.67 (d, J=6.6 Hz, 3H), 2.37 (d, J=2.0 Hz, 3H),2.05 (d, J=9.8 Hz, 2H), 1.91 (d, J=16.4 Hz, 3H), 1.66 (d, J=20.3 Hz,3H), 0.93 (q, J=16.5, 10.6 Hz, 2H).

Example 69: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (1-ethyl-3-piperidyl) methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.17-7.02 (m,4H), 6.78 (dd, J=8.5, 2.5 Hz, 1H), 6.61 (d, J=2.4 Hz, 1H), 4.48 (t,J=5.0 Hz, 2H), 4.28-4.17 (m, 1H), 4.11-3.94 (m, 3H), 3.79-3.68 (m, 4H),3.43 (dd, J=13.8, 7.6 Hz, 1H), 3.26 (bs, 1H), 3.18-3.09 (m, 1H), 3.04(bs, 1H), 2.99-2.91 (m, 2H), 2.92-2.84 (m, 2H), 2.71-2.59 (m, 2H), 2.54(bs, 1H), 2.44 (bs, 1H), 2.16-2.05 (m, 1H), 1.89 (dd, J=16.4, 8.7 Hz,2H), 1.81-1.71 (m, 1H), 1.20 (t, J=7.3 Hz, 3H).

Example 70: Synthesis of8-[(1-acetyl-4-piperidyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (1-acetyl-4-piperidyl)methyl methanesulfonate was usedinstead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.8 Hz, 1H), 7.17-7.01 (m,4H), 6.79-6.71 (m, 1H), 6.58 (s, 1H), 4.59 (d, J=13.3 Hz, 1H), 4.53-4.41(m, 2H), 4.27-4.17 (m, 1H), 3.98 (d, J=13.6 Hz, 2H), 3.91 (d, J=6.3 Hz,2H), 3.83-3.64 (m, 4H), 3.42 (dd, J=13.9, 7.6 Hz, 1H), 3.21-3.12 (m,1H), 2.98-2.82 (m, 4H), 2.75-2.60 (m, 3H), 2.13 (s, 3H), 1.92 (dd,J=25.3, 14.0 Hz, 2H), 1.45-1.21 (m, 3H).

Example 71: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,2,2-trifluoroethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that 2,2,2-trifluoroethyl methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.73 (d, J=8.8 Hz, 1H), 7.19-6.99 (m,4H), 6.84 (d, J=9.0 Hz, 1H), 6.69 (s, 1H), 4.61 (q, J=8.4 Hz, 2H), 4.50(t, J=5.1 Hz, 2H), 4.27-4.17 (m, 1H), 3.99 (d, J=13.6 Hz, 1H), 3.81-3.67(m, 4H), 3.43 (dd, J=13.9, 7.4 Hz, 1H), 3.00-2.82 (m, 4H), 2.65 (d,J=6.2 Hz, 2H).

Example 72: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(dimethylamino)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that 2-chloro-N,N-dimethyl-ethanamine hydrochloride was usedinstead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.6 Hz, 1H), 7.19-7.01 (m,4H), 6.79 (d, J=9.0 Hz, 1H), 6.62 (s, 1H), 4.48 (t, J=5.0 Hz, 2H),4.28-4.19 (m, 1H), 4.16 (t, J=5.5 Hz, 2H), 3.98 (d, J=13.8 Hz, 1H),3.82-3.69 (m, 4H), 3.43 (dd, J=13.8, 7.8 Hz, 1H), 2.99-2.85 (m, 4H),2.86-2.77 (m, 2H), 2.69-2.60 (m, 2H), 2.38 (s, 6H).

Example 73: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-morpholinoethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that 4-(2-chloroethyl)morpholine hydrochloride was used insteadof 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 7.78 (d, J=8.7 Hz, 1H), 7.13 (dd,J=9.7, 5.6 Hz, 3H), 7.01 (d, J=6.7 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 6.50(s, 1H), 4.45 (d, J=4.7 Hz, 2H), 4.12 (t, J=5.6 Hz, 3H), 3.93 (d, J=14.1Hz, 1H), 3.83 (d, J=14.9 Hz, 1H), 3.73 (d, J=4.8 Hz, 6H), 3.63 (d,J=14.8 Hz, 1H), 3.51 (dd, J=14.1, 6.2 Hz, 1H), 2.93 (dq, J=13.3, 5.5 Hz,3H), 2.81 (t, J=5.7 Hz, 3H), 2.77-2.71 (m, 1H), 2.66 (dd, J=12.3, 4.0Hz, 1H), 2.57 (q, J=6.0, 5.3 Hz, 5H), 1.31-1.20 (m, 1H).

Example 74: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(2-oxopyrrolidin-1-yl)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that 2-(2-oxopyrrolidin-1-yl)ethyl methanesulfonate was usedinstead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.7 Hz, 1H), 7.13 (d, J=9.0Hz, 3H), 7.01 (d, J=7.0 Hz, 1H), 6.67 (d, J=8.9 Hz, 1H), 6.48 (s, 1H),4.46 (d, J=4.8 Hz, 3H), 4.12 (d, J=5.3 Hz, 4H), 3.88 (dd, J=41.5, 14.5Hz, 2H), 3.79-3.43 (m, 8H), 2.93 (d, J=16.8 Hz, 3H), 2.70 (dd, J=32.9,9.3 Hz, 2H), 2.60-2.48 (m, 1H), 2.39 (t, J=8.1 Hz, 2H), 2.12-1.97 (m,3H), 1.26 (s, 1H).

Example 75: Synthesis of2-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]-N,N-diethyl-acetamide

The title compound was synthesized in the same manner as in Example 64,except that [2-(diethylamino)-2-oxo-ethyl]methanesulfonate was usedinstead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.7 Hz, 1H), 7.13 (d, J=8.9Hz, 3H), 7.02 (d, J=6.8 Hz, 1H), 6.74 (d, J=8.9 Hz, 1H), 6.55 (s, 1H),4.69 (s, 2H), 4.53-4.42 (m, 2H), 4.12 (d, J=7.8 Hz, 1H), 3.93 (d, J=14.1Hz, 1H), 3.83 (d, J=14.9 Hz, 1H), 3.76-3.57 (m, 3H), 3.52 (dd, J=14.1,6.1 Hz, 1H), 3.39 (dq, J=14.6, 7.0 Hz, 4H), 2.93 (d, J=16.7 Hz, 3H),2.74 (d, J=5.6 Hz, 1H), 2.66 (d, J=12.4 Hz, 1H), 2.55 (t, J=11.3 Hz,1H), 2.05 (s, 1H), 1.30-1.20 (m, 3H), 1.15 (t, J=7.2 Hz, 3H).

Example 76: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-oxo-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (6-oxo-3-piperidyl) methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.17-7.02 (m,4H), 6.82-6.75 (m, 1H), 6.62 (s, 1H), 4.48 (t, J=5.0 Hz, 2H), 4.28-4.17(m, 1H), 4.13-4.02 (m, 2H), 4.02-3.92 (m, 2H), 3.79-3.67 (m, 4H), 3.42(dd, J=13.8, 7.6 Hz, 1H), 2.98-2.84 (m, 4H), 2.70-2.59 (m, 2H),2.54-2.43 (m, 1H), 2.38 (dd, J=17.1, 13.5 Hz, 2H), 2.08-1.97 (m, 1H).

Example 77: Synthesis of tert-butyl

4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Example 64,except that tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate wasused instead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.09 (d, J=19.7Hz, 4H), 6.79 (d, J=9.0 Hz, 1H), 6.62 (s, 1H), 4.70-4.60 (m, 1H),4.51-4.44 (m, 2H), 4.27-4.19 (m, 1H), 3.98 (d, J=14.4 Hz, 1H), 3.85-3.64(m, 6H), 3.45 (d, J=7.4 Hz, 1H), 2.98-2.92 (m, 2H), 2.93-2.86 (m, 2H),2.71-2.62 (m, 2H), 2.04-1.89 (m, 3H), 1.76-1.60 (m, 2H), 1.49 (s, 9H).

Example 78: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 78-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

Tert-butyl4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carboxylateobtained in Example 77 was dissolved in methanol, and 4 M hydrochloricacid solution dissolved in 1,4-dioxane was slowly added thereto. Thereaction solution was stirred at room temperature, diluted with diethylether and filtered to obtain the title compound as a white solid.

Example 78-2: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 was dissolved indichloromethane, and trimethylamine and acetic anhydride were addedthereto, followed by stirring at room temperature for 3 hours. To thereaction mixture, saturated aqueous ammonium chloride solution was addedand extracted with ethyl acetate 3 times. The oily liquid obtained bydrying the combined organic layers over anhydrous sodium sulfate andconcentrated under reduced pressure was purified by flash chromatographyto obtain the title compound as a white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (d, J=8.8 Hz, 1H), 7.27-7.05 (m,4H), 6.70 (dd, J=9.0, 2.4 Hz, 1H), 6.54 (d, J=1.9 Hz, 1H), 4.65-4.49 (m,2H), 4.47-4.28 (m, 4H), 3.81-3.57 (m, 7H), 3.48-3.33 (m, 3H), 3.33-3.23(m, 2H), 3.12 (q, J=7.4 Hz, 2H), 2.03 (s, 3H), 1.97-1.80 (m, 3H),1.77-1.54 (m, 2H).

Example 79: Synthesis of8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (1-acetyl-3-piperidyl) methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (diastereomeric mixture, 400 MHz, Methanol-d₄) δ 7.72-7.65 (m,2H), 7.17-7.02 (m, 8H), 6.83-6.74 (m, 2H), 6.61 (s, 2H), 4.68-4.59 (m,1H), 4.48 (q, J=4.6 Hz, 5H), 4.23 (s, 2H), 4.10-3.93 (m, 4H), 3.86 (dd,J=14.3, 4.8 Hz, 1H), 3.81-3.68 (m, 8H), 3.66-3.48 (m, 4H), 3.43 (dd,J=14.0, 7.7 Hz, 2H), 3.20 (t, J=11.3 Hz, 1H), 2.99-2.84 (m, 8H),2.71-2.59 (m, 4H), 2.17-1.95 (m, 9H), 1.93-1.77 (m, 3H), 1.70-1.52 (m,2H).

Example 80: Synthesis of8-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that tert-butyl 4-methylsulfonyloxypyrrolidine-1-carboxylate wasused instead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (dd, J=8.8, 3.8 Hz, 1H), 7.18-7.00(m, 4H), 6.77 (t, J=8.6 Hz, 1H), 6.60 (dd, J=5.8, 2.3 Hz, 1H), 5.19-5.04(m, 1H), 4.48 (t, J=5.0 Hz, 2H), 4.30-4.18 (m, 1H), 3.97 (dd, J=14.0,3.5 Hz, 1H), 3.92-3.59 (m, 7H), 3.54-3.37 (m, 2H), 3.00-2.84 (m, 4H),2.73-2.59 (m, 2H), 2.35-2.23 (m, 1H), 2.25-2.15 (m, 1H), 2.09 (d, J=15.8Hz, 3H).

Example 81: Synthesis of8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 80,except that tert-butyl(3S)-3-methylsulfonyloxypyrrolidine-1-carboxylatewas used instead of tert-butyl4-methylsulfonyloxypyrrolidine-1-carboxylate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=8.8 Hz, 1H), 7.09 (d, J=20.4Hz, 4H), 6.81-6.72 (m, 1H), 6.61 (d, J=5.8 Hz, 1H), 5.13 (d, J=22.4 Hz,1H), 4.52-4.44 (m, 2H), 4.29-4.18 (m, 1H), 3.98 (d, J=14.1 Hz, 1H),3.83-3.62 (m, 8H), 3.43 (dd, J=14.2, 7.5 Hz, 1H), 2.99-2.81 (m, 4H),2.70-2.59 (m, 2H), 2.36-2.27 (m, 1H), 2.27-2.16 (m, 1H), 2.09 (d, J=15.7Hz, 3H).

Example 82: Synthesis of8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 80,except that tert-butyl(3R)-3-methylsulfonyloxypyrrolidine-1-carboxylatewas used instead of tert-butyl4-methylsulfonyloxypyrrolidine-1-carboxylate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.6 Hz, 1H), 7.17-7.02 (m,4H), 6.77 (t, J=7.5 Hz, 1H), 6.61 (d, J=4.8 Hz, 1H), 5.13 (d, J=22.4 Hz,1H), 4.53-4.43 (m, 2H), 4.22 (dd, J=12.1, 5.5 Hz, 1H), 3.98 (d, J=13.4Hz, 1H), 3.91-3.61 (m, 8H), 3.43 (dd, J=13.9, 7.9 Hz, 1H), 2.99-2.82 (m,4H), 2.70-2.58 (m, 2H), 2.37-2.26 (m, 1H), 2.26-2.16 (m, 1H), 2.09 (d,J=15.6 Hz, 3H).

Example 83: Synthesis of8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 83-1: Synthesis of8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The material, which is obtained by changing 4-chlorotetrahydropyrane totert-butyl 3-methylsulfonyloxyazetidine-1-carboxylate in Example 64, asa starting material was used in the same manner as in Example 78-1 toobtain the title compound.

Example 83-2: Synthesis of8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 83-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.71 (d, J=8.7 Hz, 1H), 7.19-7.00 (m,4H), 6.69 (dd, J=8.7, 2.2 Hz, 1H), 6.49 (d, J=2.3 Hz, 1H), 5.09 (dt,J=12.0, 6.5 Hz, 1H), 4.69-4.61 (m, 1H), 4.49 (t, J=5.0 Hz, 2H), 4.42(dd, J=11.0, 6.6 Hz, 1H), 4.29-4.18 (m, 2H), 4.04-3.91 (m, 2H),3.82-3.67 (m, 4H), 3.43 (dd, J=13.7, 7.7 Hz, 1H), 3.00-2.83 (m, 4H),2.72-2.58 (m, 2H), 1.93 (s, 3H).

Example 84: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-propanoylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 83-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound,except that propanoyl chloride was used instead of acetic anhydride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.71 (d, J=8.7 Hz, 1H), 7.21-7.01 (m,4H), 6.72-6.65 (m, 1H), 6.49 (d, J=2.4 Hz, 1H), 5.15-5.05 (m, 1H),4.69-4.59 (m, 1H), 4.49 (t, J=5.0 Hz, 2H), 4.46-4.38 (m, 1H), 4.28-4.17(m, 2H), 4.03-3.90 (m, 2H), 3.85-3.68 (m, 4H), 3.44 (dd, J=13.9, 7.7 Hz,1H), 3.02-2.82 (m, 4H), 2.75-2.62 (m, 2H), 2.21 (q, J=7.5 Hz, 2H), 1.12(t, J=7.5 Hz, 3H).

Example 85: Synthesis of8-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 83-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound,except that cyclopropanecarbonyl chloride was used instead of aceticanhydride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.71 (d, J=8.7 Hz, 1H), 7.20-7.02 (m,4H), 6.71 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 5.19-5.08 (m, 1H), 4.82-4.74(m, 1H), 4.49 (t, J=5.1 Hz, 2H), 4.45-4.37 (m, 1H), 4.33 (d, J=9.9 Hz,1H), 4.29-4.16 (m, 1H), 3.97 (d, J=12.2 Hz, 2H), 3.84-3.68 (m, 4H), 3.44(dd, J=13.9, 7.7 Hz, 1H), 3.00-2.84 (m, 4H), 2.74-2.61 (m, 2H),1.67-1.56 (m, 1H), 0.93-0.78 (m, 4H).

Example 86: Synthesis of methyl

3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carboxylate

8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 83-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound,except that methyl chloroformate was used instead of acetic anhydride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=8.8 Hz, 1H), 7.16-7.00 (m,4H), 6.66 (d, J=8.7 Hz, 1H), 6.46 (s, 1H), 5.10-5.00 (m, 1H), 4.54-4.35(m, 4H), 4.28-4.16 (m, 1H), 4.06-3.90 (m, 3H), 3.78-3.70 (m, 4H), 3.69(s, 3H), 3.41 (dd, J=14.0, 7.7 Hz, 1H), 2.98-2.81 (m, 4H), 2.69-2.58 (m,2H).

Example 87: Synthesis of

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride (100 mg, 0.19 mmol) obtained in Example 78-1 wasdissolved in methanol, and paraformaldehyde (57 mg, 1.9 mmol) and sodiumcyanoborohydride (36 mg, 0.57 mmmol) were added thereto. The reactionsolution was stirred at room temperature until the reaction wascompleted, a saturated aqueous ammonium chloride solution was added,stirred for 30 minutes, and then 1 N sodium hydroxide aqueous solutionwas added for basification. The mixture was extracted with ethyl acetate3 times and dried over anhydrous sodium sulfate. The pale yellow oilyliquid obtained by removing the solvent by evaporation under reducedpressure was purified by flash chromatography to obtain the titlecompound as a white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.8 Hz, 1H), 7.16-7.00 (m,4H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.56-4.41 (m,3H), 4.27-4.16 (m, 1H), 3.97 (dd, J=13.9, 3.5 Hz, 1H), 3.79-3.63 (m,4H), 3.41 (dd, J=13.9, 7.7 Hz, 1H), 2.98-2.88 (m, 2H), 2.90-2.80 (m,2H), 2.79-2.68 (m, 2H), 2.68-2.56 (m, 2H), 2.49-2.36 (m, 2H), 2.32 (s,3H), 2.10-2.01 (m, 3H), 1.90-1.76 (m, 2H).

Example 88: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 87,except that acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.17-7.03 (m,4H), 6.81-6.74 (m, 1H), 6.60 (s, 1H), 4.61-4.51 (m, 1H), 4.47 (t, J=5.0Hz, 2H), 4.28-4.16 (m, 1H), 4.02-3.92 (m, 1H), 3.82-3.68 (m, 4H), 3.43(dd, J=13.9, 7.7 Hz, 1H), 3.01-2.80 (m, 6H), 2.74-2.51 (m, 6H),2.15-2.02 (m, 2H), 1.96-1.78 (m, 2H), 1.19 (t, J=7.2 Hz, 3H).

Example 89: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 87,except that acetone was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.7 Hz, 1H), 7.16-7.01 (m,4H), 6.78 (d, J=8.8 Hz, 1H), 6.61 (s, 1H), 4.63-4.51 (m, 1H), 4.47 (t,J=4.9 Hz, 2H), 4.22 (dd, J=7.8, 4.4 Hz, 1H), 3.97 (d, J=13.9 Hz, 1H),3.81-3.66 (m, 4H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 3.10-2.98 (m, 2H),2.98-2.82 (m, 4H), 2.83-2.70 (m, 2H), 2.69-2.58 (m, 2H), 2.18-1.98 (m,3H), 1.95-1.82 (m, 2H), 1.21 (d, J=6.5 Hz, 6H).

Example 90: Synthesis of8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 87at 60° C., except that (1-ethoxycyclopropoxy)trimethylsilane was usedinstead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=9.0 Hz, 1H), 7.18-7.02 (m,4H), 6.76 (d, J=8.8 Hz, 1H), 6.59 (s, 1H), 4.58-4.41 (m, 3H), 4.28-4.17(m, 1H), 3.97 (dd, J=14.0, 3.6 Hz, 1H), 3.83-3.66 (m, 4H), 3.42 (dd,J=14.0, 7.7 Hz, 1H), 3.01-2.78 (m, 6H), 2.73-2.51 (m, 4H), 2.10-1.96 (m,2H), 1.86-1.66 (m, 3H), 0.59-0.39 (m, 4H).

Example 91: Synthesis of8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 87,except that cyclobutanone was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.10 (d, J=21.0Hz, 4H), 6.77 (d, J=8.9 Hz, 1H), 6.60 (s, 1H), 4.63-4.50 (m, 2H), 4.47(d, J=5.3 Hz, 2H), 4.29-4.18 (m, 1H), 3.97 (d, J=14.5 Hz, 1H), 3.80 (s,2H), 3.77-3.67 (m, 2H), 3.44 (dd, J=14.0, 7.5 Hz, 1H), 3.05-2.88 (m,5H), 2.86-2.74 (m, 2H), 2.71-2.63 (m, 2H), 2.56-2.35 (m, 3H), 2.22-2.11(m, 2H), 2.11-1.93 (m, 4H), 1.92-1.74 (m, 4H).

Example 92: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 87,except that oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.75-7.56 (m, 1H), 7.12 (d, J=3.1 Hz,3H), 7.06 (d, J=6.7 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.58 (d, J=2.1 Hz,1H), 4.71 (t, J=6.7 Hz, 2H), 4.62 (t, J=6.3 Hz, 2H), 4.54-4.41 (m, 3H),4.23 (s, 1H), 4.02-3.91 (m, 1H), 3.79 (s, 2H), 3.73 (s, 2H), 3.55 (t,J=6.5 Hz, 1H), 3.43 (dd, J=14.0, 7.6 Hz, H), 2.93 (dd, J=11.3, 4.6 Hz,4H), 2.68 (d, J=6.6 Hz, 2H), 2.61 (s, 2H), 2.28 (t, J=10.0 Hz, 2H), 2.04(d, J=10.2 Hz, 2H), 1.89 (d, J=36.1 Hz, 2H).

Example 93: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 83-1 as a starting material was used inthe same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.5 Hz, 1H), 7.09 (d, J=19.7Hz, 4H), 6.65 (d, J=8.9 Hz, 1H), 6.44 (s, 1H), 4.86 (t, J=5.6 Hz, 3H),4.47 (t, J=5.2 Hz, 2H), 4.29-4.17 (m, 1H), 3.98 (dd, J=13.7, 2.5 Hz,1H), 3.83 (t, J=7.5 Hz, 2H), 3.78-3.69 (m, 4H), 3.42 (dd, J=13.9, 7.8Hz, 1H), 3.28 (dd, J=8.6, 5.1 Hz, 3H), 2.98-2.82 (m, 4H), 2.70-2.58 (m,2H), 2.44 (s, 3H).

Example 94: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 83-1 as a starting material was used inthe same manner as in Example 87 to obtain the title compound, exceptthat acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.57 (d, J=8.7 Hz, 1H), 7.05-6.91 (m,4H), 6.55 (d, J=8.7 Hz, 1H), 6.34 (d, J=2.9 Hz, 1H), 4.36 (t, J=5.0 Hz,2H), 4.15-4.04 (m, 1H), 3.90-3.80 (m, 1H), 3.73 (t, J=7.7 Hz, 2H), 3.66(s, 2H), 3.61 (t, J=5.2 Hz, 2H), 3.31 (dd, J=13.9, 7.7 Hz, 1H), 3.17(dd, J=8.8, 4.9 Hz, 4H), 2.87-2.73 (m, 4H), 2.60-2.47 (m, 4H), 1.96-1.85(m, 3H), 0.92 (t, J=7.2 Hz, 3H).

Example 95: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 83-1 as a starting material was used inthe same manner as in Example 87 to obtain the title compound, exceptthat acetone was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.7 Hz, 1H), 7.18-7.01 (m,4H), 6.67 (d, J=8.9 Hz, 1H), 6.46 (s, 1H), 4.88-4.78 (m, 1H), 4.48 (t,J=5.2 Hz, 2H), 4.28-4.17 (m, 1H), 4.02-3.93 (m, 1H), 3.86-3.65 (m, 6H),3.42 (dd, J=13.9, 7.7 Hz, 1H), 3.24 (t, J=7.0 Hz, 2H), 3.00-2.83 (m,4H), 2.72-2.60 (m, 2H), 2.57-2.46 (m, 1H), 1.01 (d, J=6.2 Hz, 6H).

Example 96: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(oxetan-3-ylyl)azetidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 83-1 as a starting material was used inthe same manner as in Example 87 to obtain the title compound, exceptthat oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.7 Hz, 1H), 7.19-7.02 (m,4H), 6.67 (d, J=8.7 Hz, 1H), 6.47 (s, 1H), 4.77 (t, J=6.9 Hz, 2H), 4.50(dt, J=15.6, 5.6 Hz, 4H), 4.25 (d, J=6.3 Hz, 1H), 4.01-3.83 (m, 4H),3.82 (s, 2H), 3.73 (d, J=5.0 Hz, 2H), 3.44 (dd, J=13.9, 7.5 Hz, 1H),2.95 (s, 4H), 2.69 (d, J=6.7 Hz, 2H).

Example 97: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl3-(methylsulfonyloxymethyl)azetidin-1-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound, except that acetaldehyde was used instead ofparaformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.7 Hz, 1H), 7.17-7.01 (m,4H), 6.76 (d, J=8.8 Hz, 1H), 6.60 (s, 1H), 4.48 (t, J=5.0 Hz, 2H),4.27-4.17 (m, 1H), 4.14 (d, J=6.4 Hz, 2H), 3.98 (dd, J=13.7, 3.5 Hz,1H), 3.80-3.67 (m, 4H), 3.53-3.37 (m, 3H), 3.15 (t, J=7.2 Hz, 2H),3.01-2.89 (m, 3H), 2.90-2.80 (m, 2H), 2.70-2.61 (m, 2H), 2.57 (q, J=7.4Hz, 2H), 1.00 (t, J=7.2 Hz, 3H).

Example 98: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl4-methylsulfonyloxypyrrolidin-1-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (dd, J=8.7, 2.0 Hz, 1H), 7.11 (d,J=3.3 Hz, 3H), 7.05 (d, J=6.7 Hz, 1H), 6.72 (dd, J=8.8, 2.4 Hz, 1H),6.53 (d, J=2.4 Hz, 1H), 4.95 (d, J=6.9 Hz, 1H), 4.47 (t, J=5.3 Hz, 2H),4.22 (d, J=6.3 Hz, 1H), 3.98 (dd, J=14.0, 3.4 Hz, 1H), 3.74 (d, J=9.3Hz, 4H), 3.42 (dd, J=14.0, 7.7 Hz, 1H), 3.00-2.81 (m, 8H), 2.64 (d,J=6.2 Hz, 2H), 2.53-2.45 (m, 1H), 2.41 (s, 3H), 2.07-1.93 (m, 2H), 1.32(d, J=6.0 Hz, 1H).

Example 99: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidin-1-carboxylate totert-butyl(3S)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example83-1 as a starting material was used in the same manner as in Example 87to obtain the title compound, except that acetaldehyde was used insteadof paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=8.7 Hz, 1H), 7.10-6.95 (m,4H), 6.66 (d, J=8.9 Hz, 1H), 6.48 (s, 1H), 4.94 (s, 1H), 4.41 (t, J=5.0Hz, 2H), 4.21-4.11 (m, 1H), 3.90 (d, J=16.4 Hz, 1H), 3.72 (s, 2H), 3.66(t, J=5.1 Hz, 2H), 3.37 (dd, J=14.0, 7.5 Hz, 1H), 3.03-2.77 (m, 7H),2.72-2.53 (m, 5H), 2.40-2.29 (m, 1H), 1.98 (dd, J=10.0, 7.6 Hz, 2H),1.13 (t, J=7.3 Hz, 3H).

Example 100: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that cesium carbonate was used instead of potassium carbonate,and 2-fluoropyridine was used instead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 8.26 (d, J=5.2 Hz, 1H), 7.75 (t, J=7.7Hz, 1H), 7.38 (d, J=8.6 Hz, 1H), 7.22-6.94 (m, 7H), 6.73 (d, J=2.2 Hz,1H), 6.56 (d, J=8.7 Hz, 1H), 4.16-4.01 (m, 1H), 3.91-3.77 (m, 1H), 3.69(t, J=14.7 Hz, 2H), 3.52 (d, J=14.5 Hz, 1H), 3.06-2.87 (m, 3H), 2.80 (d,J=8.8 Hz, 1H), 2.68-2.53 (m, 2H), 2.05 (d, J=11.5 Hz, 1H), 1.63 (d,J=6.0 Hz, 1H), 1.01-0.73 (m, 1H).

Example 101: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidine-1-carboxylate totert-butyl(2R)-2-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate inExample 83-1 as a starting material was used in the same manner as inExample 87 to obtain the title compound, except that acetone was usedinstead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.08-7.03 (m,3H), 6.98 (d, J=6.7 Hz, 1H), 6.78-6.69 (m, 1H), 6.56 (d, J=2.4 Hz, 1H),4.41 (t, J=5.1 Hz, 2H), 4.16 (s, 1H), 4.03 (d, J=5.7 Hz, 2H), 3.94-3.85(m, 1H), 3.73-3.62 (m, 4H), 3.37 (dd, J=13.7, 7.6 Hz, 2H), 3.22-3.15 (m,1H), 2.95 (d, J=9.3 Hz, 1H), 2.89-2.80 (m, 4H), 2.60 (d, J=6.4 Hz, 2H),2.08 (t, J=9.4 Hz, 1H), 1.98-1.79 (m, 5H), 1.24 (d, J=6.7 Hz, 5H), 1.19(d, J=6.5 Hz, 3H).

Example 102: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl4-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.59 (d, J=8.7 Hz, 1H), 7.06 (d, J=5.1Hz, 3H), 7.00 (d, J=7.0 Hz, 1H), 6.80-6.60 (m, 1H), 6.51 (d, J=2.6 Hz,1H), 5.42 (d, J=1.7 Hz, 1H), 4.39 (t, J=5.2 Hz, 2H), 4.29-4.07 (m, 1H),4.01-3.74 (m, 5H), 3.65 (t, J=5.0 Hz, 2H), 3.47 (d, J=7.2 Hz, 2H), 3.32(d, J=12.1 Hz, 2H), 3.25 (p, J=1.7 Hz, 3H), 2.90 (s, 4H), 2.76 (t,J=12.5 Hz, 2H), 2.71-2.57 (m, 6H), 2.05-1.92 (m, 4H), 1.55 (d, J=12.9Hz, 2H), 1.11 (t, J=7.0 Hz, 1H).

Example 103: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl4-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound, except that acetaldehyde was used instead ofparaformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=8.8 Hz, 1H), 7.07 (d, J=4.4Hz, 4H), 7.00 (d, J=6.0 Hz, 1H), 6.69 (d, J=8.9 Hz, 1H), 6.52 (d, J=2.5Hz, 1H), 4.40 (t, J=5.1 Hz, 2H), 4.18 (s, 1H), 3.89 (d, J=5.2 Hz, 3H),3.79 (s, 2H), 3.66 (t, J=5.1 Hz, 2H), 3.44 (ddt, J=21.3, 13.9, 6.9 Hz,4H), 3.29 (s, 1H), 3.02 (q, J=7.4 Hz, 2H), 2.91 (s, 4H), 2.81 (t, J=12.8Hz, 2H), 2.66 (d, J=7.8 Hz, 2H), 2.03 (d, J=14.1 Hz, 4H), 1.59 (d,J=13.0 Hz, 1H), 1.26 (t, J=7.3 Hz, 5H)

Example 104: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl2-(methylsulfonyloxymethyl)morpholine-4-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.12 (d, J=4.0Hz, 3H), 7.06 (s, 1H), 6.77 (d, J=8.9 Hz, 1H), 6.60 (s, 1H), 4.48 (t,J=4.9 Hz, 2H), 4.23 (s, 1H), 4.12-3.86 (m, 5H), 3.80-3.66 (m, 5H),3.56-3.35 (m, 1H), 2.91 (dd, J=20.1, 6.0 Hz, 5H), 2.74 (d, J=11.8 Hz,1H), 2.67-2.56 (m, 2H), 2.35 (s, 3H), 2.26-2.16 (m, 1H), 2.07 (q, J=9.9,8.9 Hz, 2H).

Example 105: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl2-(methylsulfonyloxymethyl)morpholine-4-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound, except that acetaldehyde was used instead ofparaformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.12 (s, 3H),7.07 (s, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.60 (s, 1H), 4.48 (s, 2H), 4.24(s, 1H), 4.13-3.86 (m, 5H), 3.75 (d, J=22.3 Hz, 5H), 3.51-3.37 (m, 2H),2.93 (td, J=30.3, 29.0, 11.6 Hz, 6H), 2.68 (s, 2H), 2.51 (q, J=7.3 Hz,2H), 2.20 (d, J=11.2 Hz, 2H), 2.05 (d, J=10.7 Hz, 4H), 1.30 (d, J=9.4Hz, 4H), 1.15 (t, J=7.3 Hz, 3H).

Example 106: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidine-1-carboxylate to tert-butyl3-(methylsulfonyloxymethyl)pyrrolidine-1-carboxylate in Example 83-1 asa starting material was used in the same manner as in Example 87 toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.11 (d, J=3.6Hz, 3H), 7.06 (s, 1H), 6.75 (d, J=8.9 Hz, 1H), 6.58 (s, 1H), 4.47 (t,J=5.2 Hz, 2H), 4.23 (s, 1H), 3.97 (t, J=7.8 Hz, 3H), 3.74 (d, J=11.0 Hz,4H), 3.42 (dd, J=14.0, 7.7 Hz, 1H), 2.93 (d, J=5.7 Hz, 2H), 2.89-2.82(m, 3H), 2.74-2.62 (m, 4H), 2.54 (t, J=8.2 Hz, 1H), 2.43 (s, 3H), 2.12(t, J=11.3 Hz, 1H), 2.05 (d, J=9.8 Hz, 1H), 1.69 (dd, J=13.2, 6.7 Hz,1H).

Example 107: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing tert-butyl3-methylsulfonyloxyazetidin-1-carboxylate to tert-butyl3-(methylsulfonyloxymethyl)piperidine-1-carboxylate in Example 83-1 as astarting material was used in the same manner as in Example 87 to obtainthe title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.7 Hz, 1H), 7.16-7.09 (m,3H), 7.05 (d, J=6.7 Hz, 1H), 6.75 (dd, J=8.8, 2.4 Hz, 1H), 6.57 (d,J=2.3 Hz, 1H), 4.47 (t, J=5.1 Hz, 2H), 4.22 (s, 1H), 3.96 (ddd, J=15.0,11.6, 4.5 Hz, 3H), 3.86 (d, J=7.7 Hz, 1H), 3.76-3.69 (m, 4H), 3.42 (dd,J=13.9, 7.7 Hz, 1H), 3.04 (d, J=11.3 Hz, 1H), 2.93 (d, J=6.0 Hz, 3H),2.87 (d, J=5.6 Hz, 3H), 2.68-2.59 (m, 2H), 2.31 (d, J=8.8 Hz, 4H), 2.02(td, J=11.9, 11.4, 6.9 Hz, 2H), 1.93-1.74 (m, 4H), 1.66 (d, J=13.3 Hz,1H), 1.20-1.09 (m, 1H).

Example 108: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

Example 108-1: Synthesis of methyl4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate

Methyl 4-bromo-2,6-difluoro-benzoate (5.0 g, 19.9 mmol) was dissolved in50 mL of tetrahydrofura, and 60% sodium hydride (1.03 g, 25.8 mmol) andtert-butyl N-(2-hydroxyethyl)carbamate (3.7 mL, 23.9 mmol) were slowlyadded thereto at 0° C., followed by stirring at the same temperature. Tothe reaction solution saturated aqueous chloroammonium solution andextracted with ethyl acetate 3 times. The oily liquid obtained by dryingthe combined organic layers over anhydrous magnesium sulfate andconcentrating was purified by flash chromatography to obtain the titlecompound (5.07 g) as transparent liquid.

Example 108-2: Synthesis of8-bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one

Methyl 4-bromo-2-[2-(tert-butoxycarbonylamino)ethoxy]-6-fluoro-benzoate(5.07 g, 12.9 mmol) obtained in Example 108-1 was dissolved in 20 mL ofmethanol, and 4 M hydrochloric acid solution dissolved in 1,4-dioxane(20 mL, 80 mmol) was added thereto. The reaction solution was stirred atroom temperature, and sodium hydroxide aqueous solution was added underan ice bath to basify, followed by extraction with ethyl acetate 3times. The oily liquid obtained by drying the combined organic layersover anhydrous magnesium sulfate and concentrating under reducedpressure was purified by flash chromatography to obtain the solid titlecompound (870 mg).

Example 108-3: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-6-fluoro-3,4-dihydro-2H-1,4-benzoxazepin-5-one obtained inExample 108-2 as a starting material was used in the same manner as inExample 5 to obtain the title compound.

Example 108-4: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholnomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 108-3 as a starting material was used in the samemanner as in Example 22 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.12 (d, J=3.8 Hz, 3H), 7.06 (d, J=9.8Hz, 2H), 6.95 (s, 1H), 4.43 (t, J=5.6 Hz, 2H), 4.29-4.20 (m, 1H),4.03-3.94 (m, 1H), 3.85-3.76 (m, 2H), 3.76-3.65 (m, 6H), 3.54 (s, 2H),3.52-3.44 (m, 1H), 3.02-2.86 (m, 4H), 2.74-2.63 (m, 2H), 2.54-2.42 (m,4H).

Example 109: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 109-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 108-3 as a starting material was used in the samemanner as in Example 56-1 to obtain the title compound.

Example 109-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-oneas a starting material was used in the same manner as in Examples 77,78-1 and 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.09 (d, J=19.1 Hz, 4H), 6.65 (d, J=12.2Hz, 1H), 6.51 (s, 1H), 4.57-4.46 (m, 1H), 4.41 (t, J=5.7 Hz, 2H),4.28-4.16 (m, 1H), 3.97 (d, J=12.0 Hz, 1H), 3.77 (s, 2H), 3.71 (t, J=5.6Hz, 2H), 3.45 (dd, J=13.8, 7.6 Hz, 1H), 3.00-2.83 (m, 4H), 2.81-2.70 (m,2H), 2.70-2.59 (m, 2H), 2.51-2.38 (m, 2H), 2.35 (s, 3H), 2.12-1.99 (m,2H), 1.92-1.76 (m, 2H).

Example 110: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Example 110-1: Synthesis of 7-bromo-2,2-dimethyl-chroman-4-one

1-(4-Bromo-2-hydroxyphenyl)ethanone (5.0 g, 23.2 mmol) was dissolved in20 mL of methanol, and pyrrolidine (5 mL, 60.9 mmol) was added theretoand stirred for 30 minutes under an ice bath. To the reaction solutionacetone (2.5 mL, 33.7 mmol) was added, heated to reflux for 4 hours, andwater was added to terminate the reaction, followed by extraction withethyl acetate 3 times. The combined organic layers were dried overanhydrous magnesium sulfate, concentrated, dissolved in ethyl acetate,and filtered through a small amount of silica. The solution wasconcentrated under reduced pressure to obtain the title compound (4.7 g)as a crystalline solid without additional purification.

Example 110-2: Synthesis of8-bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one

7-Bromo-2,2-dimethyl-chroman-4-one (4.7 g, 18.6 mmol) obtained inExample 110-1 was dissolved in 25 mL of methanesulfonic acid, and sodiumazide (1.81 g, 27.9 mmol) was slowly added thereto under an ice bath.The reaction solution was stirred at room temperature for 5 hours, and 1M sodium hydroxide aqueous solution was slowly added while maintainingat 0° C. under an ice bath. After basifying the reaction solution to pH10 or more, ethyl acetate was added thereto and extracted 3 times. Thecombined organic layers were dried over anhydrous magnesium sulfate, thesolvent was removed by evaporation under reduced pressure, and thenrecrystallized from dichloromethane and hexane to obtain the solid titlecompound.

Example 110-3: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

8-Bromo-2,2-dimethyl-3,4-dihydro-1,4-benzoxazepin-5-one obtained inExample 110-2 as a starting material was used in the same manner as inExample 5 to obtain the title compound.

Example 110-4: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one obtained in Example 110-3 as a startingmaterial was used in the same manner as in Example 56-1 to obtain thetitle compound.

Example 110-5: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-1,4-benzoxazepin-5-onedihydrochloride

The material obtained in Example 110-4 as a starting material was usedin the same manner as in Examples 77 and 78-1 to obtain the titlecompound.

Example 110-6: Synthesis of

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

The material obtained in Example 110-5 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (d, J=8.0 Hz, 1H), 7.09 (d, J=19.8Hz, 4H), 6.81 (d, J=8.9 Hz, 1H), 6.52 (s, 1H), 4.58-4.48 (m, 1H),4.32-4.22 (m, 1H), 4.03 (d, J=13.7 Hz, 1H), 3.76 (s, 2H), 3.50 (s, 2H),3.41 (dd, J=10.0, 3.2 Hz, 1H), 2.97-2.90 (m, 2H), 2.91-2.76 (m, 4H),2.71-2.59 (m, 2H), 2.59-2.41 (m, 4H), 2.14-1.98 (m, 2H), 1.94-1.78 (m,2H), 1.43 (s, 3H), 1.34 (s, 3H), 1.16 (t, J=7.2 Hz, 3H).

Example 111: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one as a starting material was used in the samemanner as in Example 22 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.9Hz, 1H), 7.17-7.02 (m, 4H), 7.00 (s, 1H), 4.34-4.24 (m, 1H), 4.06 (dd,J=13.7, 2.6 Hz, 1H), 3.78 (s, 2H), 3.71 (t, J=4.7 Hz, 4H), 3.56 (s, 2H),3.53-3.38 (m, 3H), 2.99-2.81 (m, 4H), 2.72-2.58 (m, 2H), 2.48 (t, J=4.8Hz, 4H), 1.43 (s, 3H), 1.33 (s, 3H).

Example 112: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-1,4-benzoxazepin-5-one

The material obtained in Example 110-5 as a starting material was usedin the same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.57 (d, J=8.6 Hz, 1H), 7.17-7.02 (m,4H), 6.81 (d, J=8.7 Hz, 1H), 6.52 (s, 1H), 4.56-4.46 (m, 1H), 4.33-4.21(m, 1H), 4.03 (d, J=13.3 Hz, 1H), 3.75 (s, 2H), 3.50 (s, 2H), 3.40 (dd,J=14.0, 8.1 Hz, 1H), 2.98-2.81 (m, 4H), 2.80-2.66 (m, 2H), 2.66-2.54 (m,2H), 2.51-2.39 (m, 2H), 2.34 (s, 3H), 2.10-1.98 (m, 2H), 1.89-1.76 (m,2H), 1.43 (s, 3H), 1.34 (s, 3H).

Example 113: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylmethoxy)-3H-1,4-benzoxazepin-5-one

The material obtained in Example 110-4 as a starting material was usedin the same manner as in Example 56-2 to obtain the title compound,except that 4-(chloromethyl)pyridine hydrochloride was used instead of3-(chloromethyl)pyridine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 8.56 (d, J=5.2 Hz, 2H), 7.61 (d, J=8.6Hz, 1H), 7.54 (d, J=5.1 Hz, 2H), 7.17-7.00 (m, 4H), 6.90 (d, J=8.8 Hz,1H), 6.62 (s, 1H), 5.25 (s, 2H), 4.32-4.22 (m, 1H), 4.03 (d, J=13.8 Hz,1H), 3.76 (s, 2H), 3.50 (s, 2H), 3.41 (dd, J=13.9, 8.2 Hz, 1H),2.97-2.82 (m, 4H), 2.66-2.57 (m, 2H), 1.42 (s, 3H), 1.32 (s, 3H).

Example 114: Synthesis of8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

The material obtained in Example 110-4 as a starting material was usedin the same manner as in Example 83 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=8.6 Hz, 1H), 7.16-7.02 (m,4H), 6.72 (d, J=8.1 Hz, 1H), 6.44 (s, 1H), 5.15-5.05 (m, 1H), 4.69-4.59(m, 1H), 4.47-4.37 (m, 1H), 4.33-4.19 (m, 2H), 4.10-4.00 (m, 1H),4.01-3.92 (m, 1H), 3.76 (s, 2H), 3.50 (s, 2H), 3.40-3.33 (m, 1H),2.99-2.81 (m, 4H), 2.67-2.58 (m, 2H), 1.93 (s, 3H), 1.43 (s, 3H), 1.34(s, 3H).

Example 115: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one

Example 115-1: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one as a startingmaterial was used in the same manner as in Example 5 to obtain the titlecompound.

Example 115-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 22 toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (d, J=8.0 Hz, 1H), 7.15-7.08 (m,2H), 7.09-7.03 (m, 1H), 7.01 (d, J=7.0 Hz, 2H), 4.29-4.20 (m, 1H), 3.94(dd, J=14.0, 4.0 Hz, 1H), 3.78 (s, 2H), 3.72 (t, J=4.7 Hz, 4H),3.65-3.57 (m, 2H), 3.55 (s, 2H), 3.50 (t, J=7.4 Hz, 1H), 3.48-3.36 (m,3H), 3.00-2.88 (m, 4H), 2.86 (s, 3H), 2.69 (t, J=5.4 Hz, 2H), 2.49 (s,4H).

Example 116: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 10 toobtain the title compound, except that 3,3,3-trifluoropropylboronic acidwas used instead of methylboronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J=7.8 Hz, 1H), 7.14 (q, J=5.6,5.1 Hz, 3H), 7.09-6.91 (m, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.67 (s, 1H),4.11 (s, 1H), 3.98-3.76 (m, 2H), 3.73-3.48 (m, 4H), 3.41 (dt, J=11.8,6.0 Hz, 1H), 3.30 (dt, J=10.8, 5.3 Hz, 1H), 2.94 (d, J=11.3 Hz, 2H),2.87 (d, J=8.0 Hz, 5H), 2.84 (s, 1H), 2.75 (s, 1H), 2.68 (dd, J=12.5,4.2 Hz, 1H), 2.65-2.56 (m, 1H), 2.39 (dq, J=20.0, 10.5 Hz, 2H),1.00-0.78 (m, 2H).

Example 117: Synthesis of8-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 10 toobtain the title compound, except that cyclohexylmethylboronic acid wasused instead of methylboronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.53 (d, J=7.8 Hz, 1H), 7.24-7.04 (m,3H), 7.02 (d, J=6.7 Hz, 1H), 6.78 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 4.12(s, 1H), 3.85 (dd, J=17.6, 14.1 Hz, 2H), 3.74-3.52 (m, 4H), 3.39 (dt,J=11.7, 5.9 Hz, 1H), 3.33-3.21 (m, 1H), 2.95 (s, 1H), 2.82 (s, 2H), 2.77(d, J=9.0 Hz, 1H), 2.71-2.59 (m, 2H), 2.46 (d, J=7.1 Hz, 2H), 1.68 (d,J=11.4 Hz, 5H), 1.32-1.13 (m, 5H), 0.93 (q, J=13.8, 12.4 Hz, 3H).

Example 118: Synthesis of8-(cyclohexen-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 10 toobtain the title compound, except that2-(cyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was usedinstead of methylboronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J=8.0 Hz, 1H), 7.19-7.07 (m,3H), 7.01 (t, J=6.2 Hz, 2H), 6.86 (s, 1H), 6.17 (s, 1H), 4.12 (d, J=7.3Hz, 1H), 3.97-3.76 (m, 2H), 3.70-3.44 (m, 4H), 3.38 (dt, J=11.9, 6.1 Hz,1H), 3.27 (dt, J=10.6, 5.2 Hz, 1H), 2.91 (d, J=5.3 Hz, 4H), 2.85 (s,3H), 2.75 (t, J=7.8 Hz, 1H), 2.70-2.56 (m, 2H), 2.40 (s, 2H), 2.25-2.18(m, 2H), 2.17 (s, 1H), 2.05 (s, 1H), 1.78 (q, J=6.2, 5.3 Hz, 2H), 1.67(t, J=5.8 Hz, 2H), 1.30-1.20 (m, 1H).

Example 119: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 10 toobtain the title compound, except that4,4,5,5-tetramethyl-2-[4-(trifluoromethyl)cyclohexen-1-yl]-1,3,2-dioxaborolanewas used instead of methylboronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J=7.9 Hz, 1H), 7.19-7.07 (m,3zH), 7.00 (dd, J=13.6, 7.3 Hz, 2H), 6.84 (s, 1H), 6.11 (d, J=5.1 Hz,1H), 4.11 (t, J=7.1 Hz, 2H), 3.95-3.76 (m, 2H), 3.65 (s, 1H), 3.60 (dd,J=10.0, 4.6 Hz, 3H), 3.39 (dt, J=10.4, 5.1 Hz, 1H), 3.29 (dq, J=10.4,5.2 Hz, 1H), 2.92 (q, J=8.0, 6.0 Hz, 4H), 2.85 (s, 3H), 2.75 (dd,J=10.8, 5.0 Hz, 1H), 2.69-2.58 (m, 2H), 2.57-2.43 (m, 2H), 2.42-2.24 (m,1H), 2.23-2.14 (m, 1H), 2.05 (s, 1H), 1.69 (qd, J=11.9, 5.8 Hz, 1H),1.43-1.18 (m, 1H).

Example 120: Synthesis of tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2,3-dihydro-1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 10 toobtain the title compound, except that4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylatewas used instead of methylboronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J=8.0 Hz, 1H), 7.18-7.08 (m,3H), 7.01 (t, J=8.8 Hz, 2H), 6.84 (s, 1H), 6.08 (s, 1H), 4.21-4.04 (m,3H), 4.01-3.75 (m, 2H), 3.74-3.52 (m, 5H), 3.48-3.35 (m, 1H), 3.36-3.24(m, 1H), 2.92 (s, 2H), 2.85 (s, 3H), 2.74 (s, 1H), 2.72-2.56 (m, 2H),2.52 (s, 2H), 2.05 (s, 1H), 1.49 (s, 7H), 1.31-1.21 (m, 2H).

Example 121: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Example 121-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-oneas a starting material was used in the same manner as in Example 56-1 toobtain the title compound

Example 121-2: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that (1-acetyl-4-piperidyl) methanesulfonate was used instead of4-chlorotetrahydropyran.

¹H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.2Hz, 3H), 7.02 (d, J=6.7 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 6.38 (s, 1H),4.59 (s, 1H), 4.11 (t, J=7.1 Hz, 2H), 3.99-3.81 (m, 1H), 3.84-3.72 (m,2H), 3.74-3.56 (m, 6H), 3.42 (dd, J=11.6, 5.8 Hz, 2H), 3.36-3.25 (m,1H), 2.91 (d, J=8.7 Hz, 3H), 2.81 (s, 3H), 2.75 (s, 1H), 2.69-2.53 (m,2H), 2.13 (d, J=1.5 Hz, 3H), 2.05 (d, J=1.5 Hz, 1H), 1.98-1.77 (m, 5H),1.44-1.15 (m, 2H), 1.09-0.81 (m, 1H).

Example 122: Synthesis of8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 83 to obtain the title compound.

¹H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J=8.4 Hz, 1H), 7.19-7.07 (m,3H), 7.02 (d, J=6.7 Hz, 1H), 6.44-6.16 (m, 2H), 4.97 (t, J=5.7 Hz, 1H),4.49 (t, J=8.0 Hz, 1H), 4.39 (dd, J=10.9, 6.6 Hz, 1H), 4.28-3.99 (m,4H), 3.95-3.72 (m, 2H), 3.75-3.50 (m, 4H), 3.52-3.26 (m, 2H), 2.93 (q,J=9.0, 6.9 Hz, 3H), 2.81 (s, 3H), 2.78-2.54 (m, 3H), 2.05 (s, 1H), 1.92(s, 3H), 1.26 (t, J=7.2 Hz, 1H).

Example 123: Synthesis of8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material and theintermediate obtained by changing 4-chlorotetrahydropyran totert-butyl(3S)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example 64were used in the same manner as in Example 78 to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.51 (dd, J=8.7, 3.2 Hz, 1H), 7.29-7.03(m, 4H), 6.68-6.34 (m, 2H), 5.15 (d, J=22.7 Hz, 1H), 4.27 (s, 1H),3.99-3.84 (m, 3H), 3.79-3.57 (m, 6H), 3.55-3.39 (m, 2H), 3.01 (d, J=8.8Hz, 4H), 2.81 (d, J=15.8 Hz, 5H), 2.40-2.14 (m, 2H), 2.16-1.90 (m, 5H),1.31 (s, 3H).

Example 124: Synthesis of8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material and theintermediate obtained by changing 4-chlorotetrahydropyran totert-butyl(3R)-3-methylsulfonyloxypyrrolidin-1-carboxylate in Example 64were used in the same manner as in Example 78 to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.57-7.45 (m, 1H), 7.15 (d, J=4.5 Hz,3H), 7.09 (s, 1H), 6.60 (d, J=7.9 Hz, 1H), 6.48 (d, J=5.6 Hz, 1H), 5.15(d, J=22.7 Hz, 1H), 4.27 (s, 1H), 3.90 (d, J=14.7 Hz, 3H), 3.79-3.58 (m,5H), 3.59-3.41 (m, 2H), 2.99 (s, 4H), 2.80 (d, J=23.3 Hz, 5H), 2.31 (s,1H), 2.23 (s, 1H), 2.18-1.98 (m, 4H), 1.96 (s, 1H), 1.28 (d, J=20.7 Hz,2H).

Example 125: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

Example 125-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzodiazepin-5-onedihydrochloride

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Examples 77 and 78-1 to obtain the titlecompound.

Example 125-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 125-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (d, J=8.4 Hz, 1H), 7.13 (d, J=4.4Hz, 3H), 7.08 (s, 1H), 6.62 (d, J=8.7 Hz, 1H), 6.50 (s, 1H), 4.25 (s,1H), 4.00-3.78 (m, 3H), 3.61 (d, J=5.7 Hz, 2H), 3.52-3.38 (m, 2H), 2.89(d, J=52.2 Hz, 8H), 2.73 (s, 3H), 2.49 (s, 3H), 2.05 (d, J=11.4 Hz, 3H),1.94 (s, 2H).

Example 126: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 125-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.50 (d, J=8.6 Hz, 1H), 7.13 (d, J=3.0Hz, 3H), 7.07 (d, J=6.9 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 6.51 (s, 1H),4.65 (d, J=9.6 Hz, 1H), 4.25 (s, 1H), 3.91 (dd, J=13.9, 3.9 Hz, 1H),3.84 (s, 2H), 3.62 (t, J=5.8 Hz, 2H), 3.51-3.36 (m, 3H), 3.18-3.04 (m,2H), 2.96 (s, 4H), 2.85 (d, J=12.9 Hz, 6H), 2.73 (t, J=5.5 Hz, 2H), 2.14(s, 2H), 2.09-1.93 (m, 3H), 1.35-1.10 (m, 5H).

Example 127: Synthesis of8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 125-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat cyclobutanone was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.41 (d, J=8.5 Hz, 1H), 7.05 (d, J=3.0Hz, 3H), 6.99 (s, 1H), 6.53 (d, J=8.6 Hz, 1H), 6.41 (s, 1H), 4.47 (s,1H), 4.15 (d, J=6.7 Hz, 1H), 3.85 (d, J=14.6 Hz, 1H), 3.71 (s, 2H), 3.54(s, 2H), 3.37 (dt, J=11.7, 6.3 Hz, 2H), 2.92-2.81 (m, 4H), 2.75 (s, 3H),2.68-2.54 (m, 4H), 2.32 (s, 2H), 2.06 (s, 2H), 1.97 (d, J=8.7 Hz, 4H),1.88 (d, J=9.6 Hz, 1H), 1.79-1.62 (m, 4H).

Example 128: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahydrofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 125-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat tetrahydrofuran-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.48 (d, J=8.6 Hz, 1H), 7.12 (d, J=4.2Hz, 3H), 7.06 (s, 1H), 6.60 (d, J=8.6 Hz, 1H), 6.47 (s, 1H), 4.51 (d,J=7.7 Hz, 1H), 4.23 (t, J=5.9 Hz, 1H), 3.93 (tt, J=12.0, 4.8 Hz, 6H),3.78 (s, 5H), 3.69-3.51 (m, 5H), 3.48-3.36 (m, 2H), 3.06 (t, J=7.3 Hz,1H), 2.94 (d, J=5.3 Hz, 2H), 2.90 (d, J=4.6 Hz, 2H), 2.82 (s, 3H),2.74-2.64 (m, 3H), 2.51 (t, J=10.1 Hz, 1H), 2.41 (t, J=9.8 Hz, 1H), 2.16(dd, J=13.1, 6.9 Hz, 2H), 2.04 (d, J=9.5 Hz, 3H), 1.94-1.71 (m, 5H).

Example 129: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 125-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55-7.37 (m, 1H), 7.12 (d, J=5.1 Hz,3H), 7.06 (d, J=6.8 Hz, 1H), 6.60 (d, J=8.6 Hz, 1H), 6.47 (s, 1H), 4.71(t, J=6.7 Hz, 2H), 4.62 (t, J=6.2 Hz, 2H), 4.53 (s, 1H), 4.23 (s, 1H),3.94 (s, 1H), 3.79 (s, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.64-3.51 (m, 3H),3.44 (dt, J=13.1, 6.7 Hz, 2H), 2.93 (dd, J=11.8, 4.7 Hz, 4H), 2.82 (s,3H), 2.68 (d, J=7.8 Hz, 2H), 2.62 (d, J=12.0 Hz, 2H), 2.29 (t, J=9.8 Hz,2H), 2.04 (d, J=10.2 Hz, 2H), 1.85 (s, 2H).

Example 130: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 68 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.50 (dd, J=8.6, 1.7 Hz, 1H), 7.12 (t,J=2.5 Hz, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.61 (dd, J=8.5, 2.5 Hz, 1H),6.51 (d, J=2.4 Hz, 1H), 4.28-4.20 (m, 1H), 4.08 (d, J=5.3 Hz, 2H), 3.92(dd, J=14.2, 3.9 Hz, 1H), 3.78 (s, 2H), 3.62 (dt, J=8.6, 4.5 Hz, 2H),3.42 (ddd, J=21.1, 15.3, 6.7 Hz, 2H), 3.17 (dt, J=10.1, 4.3 Hz, 1H),2.99-2.87 (m, 5H), 2.87-2.81 (m, 3H), 2.67 (t, J=4.7 Hz, 2H), 2.57 (d,J=1.8 Hz, 3H), 2.47 (q, J=8.9 Hz, 1H), 2.14 (dd, J=12.4, 8.3 Hz, 1H),2.05 (d, J=10.0 Hz, 2H), 1.93-1.73 (m, 4H), 1.31 (s, 3H).

Example 131: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 106 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (d, J=8.5 Hz, 1H), 7.11 (s, 3H),7.06 (s, 1H), 6.58 (d, J=8.7 Hz, 1H), 6.48 (s, 1H), 4.23 (s, 1H),4.07-3.87 (m, 3H), 3.76 (s, 2H), 3.61 (s, 2H), 3.51-3.40 (m, 2H), 2.91(dd, J=19.1, 5.4 Hz, 5H), 2.84 (s, 3H), 2.68 (d, J=8.9 Hz, 5H), 2.56 (d,J=8.0 Hz, 1H), 2.43 (d, J=2.1 Hz, 3H), 2.05 (d, J=9.6 Hz, 3H), 1.71 (d,J=7.2 Hz, 1H), 1.57 (s, 1H), 0.91 (s, 2H).

Example 132: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 98 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (d, J=8.5 Hz, 1H), 7.11 (s, 3H),7.07 (s, 1H), 6.53 (d, J=8.6 Hz, 1H), 6.44 (s, 1H), 4.98 (s, 1H), 4.23(s, 1H), 3.93 (d, J=13.8 Hz, 1H), 3.77 (s, 2H), 3.62 (s, 2H), 3.44 (dd,J=14.5, 7.2 Hz, 2H), 2.91 (dd, J=18.9, 6.2 Hz, 6H), 2.83 (s, 3H), 2.66(d, J=7.7 Hz, 2H), 2.49 (d, J=8.0 Hz, 1H), 2.42 (s, 3H), 2.05 (d, J=10.2Hz, 3H), 1.31 (s, 4H).

Example 133: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 107 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.48 (d, J=8.5 Hz, 1H), 7.11 (d, J=4.7Hz, 3H), 7.06 (s, 1H), 6.57 (d, J=8.6 Hz, 1H), 6.47 (s, 1H), 4.22 (s,1H), 4.00-3.84 (m, 4H), 3.76 (s, 2H), 3.61 (d, J=5.4 Hz, 2H), 3.44 (dd,J=14.2, 7.8 Hz, 2H), 3.05 (d, J=12.9 Hz, 1H), 2.93 (d, J=6.0 Hz, 5H),2.85 (d, J=16.2 Hz, 6H), 2.65 (d, J=7.2 Hz, 2H), 2.30 (dd, J=10.2, 1.7Hz, 5H), 2.14 (s, 2H), 2.09-1.81 (m, 4H), 1.77 (s, 1H).

Example 134: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 56-2 to obtain the title compound,except that (3-fluoro-4-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 8.50 (s, 1H), 8.44 (d, J=5.0 Hz, 1H),7.67 (t, J=5.8 Hz, 1H), 7.52 (dd, J=8.7, 2.0 Hz, 1H), 7.20-7.00 (m, 4H),6.68 (dd, J=8.7, 2.6 Hz, 1H), 6.60 (d, J=2.8 Hz, 1H), 5.33 (s, 2H), 4.23(s, 1H), 3.95-3.87 (m, 1H), 3.77 (s, 2H), 3.62 (s, 2H), 3.49-3.37 (m,3H), 2.92 (dd, J=15.9, 5.2 Hz, 4H), 2.84 (d, J=2.0 Hz, 3H), 2.74-2.62(m, 2H), 1.31 (s, 1H).

Example 135: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;dihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in Example 121-1 as a starting material andchanging 4-chlorotetrahydropyran to tert-butyl3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. Theobtained intermediate was dissolved in methanol, and 4 N hydrochloricacid solution dissolved in 1,4-dioxane was added thereto. The reactionsolution was stirred at room temperature until the reaction wasterminated, diluted with ethyldiethyl ether and filtered to obtain thetitle compound as a white solid in the form of dihydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.5 Hz, 1H), 7.31 (q, J=7.5Hz, 3H), 7.24 (t, J=7.6 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.89 (s, 1H),5.06 (d, J=44.3 Hz, 2H), 4.74-4.58 (m, 1H), 4.49 (td, J=15.4, 14.0, 7.3Hz, 2H), 3.93-3.86 (m, 1H), 3.80 (d, J=9.6 Hz, 1H), 3.74-3.63 (m, 6H),3.60 (s, 1H), 3.52 (d, J=15.3 Hz, 2H), 3.44-3.35 (m, 2H), 3.25-3.14 (m,1H), 3.02 (s, 3H), 2.44-2.30 (m, 1H), 2.19 (d, J=15.7 Hz, 1H).

Example 136: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 135 as a starting material was used inthe same manner as in Example 87 to obtain the title compound, exceptthat acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (dd, J=8.6, 1.9 Hz, 1H), 7.12 (d,J=3.1 Hz, 3H), 7.06 (d, J=6.7 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 6.53 (d,J=2.6 Hz, 1H), 4.67 (d, J=48.8 Hz, 1H), 4.52 (s, 1H), 4.23 (s, 1H), 3.92(dd, J=13.7, 3.8 Hz, 1H), 3.78 (s, 2H), 3.62 (s, 2H), 3.45 (dd, J=14.4,7.6 Hz, 2H), 3.14-3.02 (m, 1H), 2.94 (d, J=5.2 Hz, 3H), 2.90 (d, J=4.6Hz, 2H), 2.83 (d, J=1.8 Hz, 3H), 2.68 (t, J=5.4 Hz, 2H), 2.55 (d, J=7.2Hz, 1H), 2.46 (d, J=8.2 Hz, 0H), 2.34 (t, J=10.8 Hz, 1H), 2.21 (s, 1H),1.77 (dd, J=12.9, 8.8 Hz, 1H), 1.19-1.11 (m, 3H).

Example 137: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Example 137-1: Synthesis of8-(8-azabicyclo[3.2.1]octan-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-onedihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in Example 121-1 as a starting material andchanging 4-chlorotetrahydropyran to tert-butyl3-methylsulfonyloxy-8-azabicyclo [3.2.1]octane-8-carboxylate in Example64. The obtained intermediate was dissolved in methanol, and 4 Nhydrochloric acid solution dissolved in 1,4-dioxane was added thereto.The reaction solution was stirred at room temperature until the reactionwas terminated, diluted with ethyldiethyl ether and filtered to obtainthe title compound as a white solid in the form of dihydrochloride.

Example 137-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 137-1 as a starting material was usedin the same manner as in Example 87 to obtain the title compound, exceptthat acetaldehyde was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66-7.39 (m, 1H), 7.12 (d, J=4.9 Hz,3H), 7.05 (d, J=6.7 Hz, 1H), 6.63 (d, J=8.6 Hz, 1H), 6.45 (d, J=2.4 Hz,1H), 4.80 (dq, J=10.7, 5.6, 4.9 Hz, 1H), 4.22 (d, J=8.0 Hz, 1H),3.94-3.87 (m, 1H), 3.77 (s, 2H), 3.69 (s, 2H), 3.61 (dd, J=7.5, 3.6 Hz,2H), 3.43 (dt, J=11.7, 6.2 Hz, 2H), 2.93 (d, J=5.5 Hz, 2H), 2.89 (d,J=5.3 Hz, 2H), 2.82 (s, 4H), 2.71-2.54 (m, 2H), 2.30-2.13 (m, 4H), 2.03(d, J=1.6 Hz, 1H), 1.97-1.84 (m, 5H), 1.24 (t, J=7.1 Hz, 4H).

Example 138: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(2-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one;dihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in Example 121-1 as a starting material andchanging 4-chlorotetrahydropyran to tert-butyl2-methyl-4-methylsulfonyloxy-piperidine-1-carboxylate in Example 64. Theobtained intermediate was dissolved in methanol, and 4 N hydrochloricacid solution dissolved in 1,4-dioxane was added thereto. The reactionsolution was stirred at room temperature until the reaction wasterminated, diluted with ethyldiethyl ether and filtered to obtain thetitle compound as a white solid in the form of dihydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=8.6 Hz, 1H), 7.32 (q, J=7.7,7.1 Hz, 3H), 7.23 (d, J=7.7 Hz, 1H), 6.87 (d, J=8.9 Hz, 1H), 6.76 (s,1H), 4.75 (d, J=11.8 Hz, 1H), 4.74-4.62 (m, 1H), 4.49 (td, J=15.2, 12.9,6.6 Hz, 2H), 3.89 (s, 1H), 3.84-3.75 (m, 1H), 3.73-3.61 (m, 3H), 3.51(t, J=17.0 Hz, 3H), 3.44-3.36 (m, 2H), 3.20 (q, J=13.8 Hz, 2H), 3.00 (s,3H), 2.42 (t, J=13.0 Hz, 1H), 1.80 (q, J=11.8, 10.8 Hz, 1H), 1.68-1.57(m, 1H), 1.42 (d, J=6.4 Hz, 2H), 1.37 (d, J=6.5 Hz, 1H).

Example 139: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 121-1 as a starting material was usedin the same manner as in Example 56-2 to obtain the title compound,except that (5-fluoro-2-pyridyl)methyl methanesulfonate was used insteadof 3-(chloromethyl)pyridine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 8.49 (s, 1H), 7.80-7.62 (m, 2H), 7.50(d, J=8.5 Hz, 1H), 7.11 (d, J=3.6 Hz, 3H), 7.06 (s, 1H), 6.65 (d, J=8.7Hz, 1H), 6.59 (s, 1H), 5.23 (s, 2H), 4.23 (s, 1H), 3.92 (d, J=13.8 Hz,1H), 3.77 (s, 2H), 3.62 (d, J=5.4 Hz, 2H), 3.44 (dd, J=13.3, 6.9 Hz,2H), 2.94 (d, J=5.5 Hz, 2H), 2.89 (d, J=5.2 Hz, 2H), 2.82 (s, 3H),2.71-2.60 (m, 2H).

Example 140: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

Example 140-1: Synthesis of methyl4-bromo-2-[2-(tert-butoxycarbonylamino)propoxy]benzoate

Methyl 4-bromo-2-hydroxy-benzoate (3 g, 12.98 mmol), Cs₂CO₃ (12.7 g,51.95 mmol) and[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate (7 mL,25.98 mmol) were dissolved in acetonitrile, stirred for one day andheated to reflux. The reaction solution was cooled to room temperature,and distilled water was added thereto, followed by dilution with ethylacetate. The combined organic layers were dried over anhydrous magnesiumsulfate, concentrated and purified by flash chromatography to obtain thetitle compound.

Example 140-2: Synthesis of methyl 2-(2-aminopropoxy)-4-bromo-benzoatehydrochloride

The material obtained in Example 140-1 as a starting material wasdissolved in methanol, and 4 N hydrochloric acid solution dissolved in1,4-dioxane was added thereto, followed by stirring at room temperature.The reaction solution was concentrated under reduced pressure to obtainthe title compound without additional purification.

Example 140-3: Synthesis of8-bromo-2-methyl-3,4-dihydro-2H-1,4-benzoxazepin-5-one

The material (2.3 g, 8.01 mmol) obtained in Example 140-2 was dissolvedin toluene, and triethylamine was added thereto. The reaction solutionwas stirred and heated to reflux. After confirming that the reaction wascomplete, the reaction solution was cooled to room temperature, and thesolvent was removed under reduced pressure. The concentrate was purifiedby flash chromatography to obtain the title compound.

Example 140-4: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 140-3 as a starting material was usedin the same manner as in Example 5 to obtain the title compound.

Example 140-5: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-hydroxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 140-4 as a starting material was usedin the same manner as in Example 56-1 to obtain the title compound.

Example 140-6: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

The material obtained in Example 140-5 as a starting material was usedin the same manner as in Examples 77 and 78-1 to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.4Hz, 3H), 7.23 (s, 1H), 6.93-6.84 (m, 1H), 6.67 (s, 1H), 4.82 (s, 2H),4.68 (d, J=16.0 Hz, 1H), 4.48 (d, J=10.0 Hz, 2H), 4.01-3.83 (m, 3H),3.70 (d, J=15.8 Hz, 2H), 3.58-3.36 (m, 8H), 3.26 (d, J=13.3 Hz, 3H),3.08 (d, J=26.7 Hz, 1H), 2.21 (s, 2H), 2.05 (d, J=14.1 Hz, 3H), 1.76 (s,1H), 1.34 (dd, J=14.1, 6.4 Hz, 3H).

Example 141: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 140 as a starting material was used inthe same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.8 Hz, 1H), 7.10 (d, J=21.1Hz, 3H), 6.80 (s, 1H), 6.57 (s, 1H), 4.55 (s, 1H), 4.25 (s, 1H), 4.15(d, J=14.1 Hz, 1H), 3.79 (s, 2H), 3.63 (d, J=14.6 Hz, 1H), 3.49 (q,J=7.6, 6.7 Hz, 1H), 3.27-3.15 (m, 1H), 2.93 (d, J=13.9 Hz, 3H), 2.84 (s,2H), 2.71-2.61 (m, 2H), 2.56 (s, 2H), 2.42 (s, 2H), 2.06 (s, 2H), 1.88(s, 2H), 1.31 (dd, J=16.5, 6.5 Hz, 3H).

Example 142: Synthesis of(2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140 as a starting material was used in the same manner as inExample 83 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.6 Hz, 1H), 7.19-7.02 (m,4H), 6.70 (d, J=8.7 Hz, 1H), 6.47 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.80(s, 1H), 4.65 (t, J=8.5 Hz, 1H), 4.42 (dd, J=11.1, 6.7 Hz, 1H), 4.23 (d,J=10.2 Hz, 2H), 4.14 (d, J=13.8 Hz, 1H), 3.97 (d, J=11.3 Hz, 1H), 3.81(s, 2H), 3.64 (d, J=15.5 Hz, 1H), 3.50 (dd, J=15.9, 7.5 Hz, 1H),3.29-3.20 (m, 1H), 2.95 (s, 4H), 2.68 (t, J=6.9 Hz, 2H), 1.93 (s, 3H),1.34 (d, J=6.3 Hz, 4H).

Example 143: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140 as a starting material was used in the same manner as inExample 141 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.8 Hz, 1H), 7.17-7.02 (m,4H), 6.79 (d, J=8.8 Hz, 1H), 6.57 (s, 1H), 4.79 (s, 1H), 4.56 (s, 1H),4.24 (s, 1H), 4.14 (d, J=12.2 Hz, 1H), 3.79 (s, 2H), 3.69-3.59 (m, 1H),3.50 (dd, J=15.6, 7.6 Hz, 1H), 3.24 (dd, J=13.8, 8.1 Hz, 1H), 2.98-2.80(m, 6H), 2.63 (dt, J=24.4, 8.0 Hz, 4H), 2.05 (d, J=13.3 Hz, 2H), 1.92(d, J=18.6 Hz, 2H), 1.33 (d, J=6.4 Hz, 3H).

Example 144: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

Example 144-1: Synthesis of2,6-dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide

2,6-Dichloropyridine-3-carboxylic acid (5.0 g, 26 mmol) was dissolved indichloromethane, and oxalyl chloride (3.3 mL, 39 mmol) and a catalyticamount of dimethylformamide were added thereto. The reaction solutionwas stirred at room temperature and concentrated under reduced pressureto obtain 2,6-dichloropyridine-3-carbonyl chloride without additionalpurification. 1-[(4-Methoxyphenyl)methylamino]propan-2-ol (1.3 g, 7.2mmol) and K₂CO₃ (2.2 g, 15.8 mmol) were dissolved in dichloromethane,and 2,6-dichloropyridine-3-carbonyl chloride (1.6 g, 7.6 mmol) dissolvedin dichloromethane was slowly added thereto under an ice bath. Thereaction solution was stirred at the same temperature for 1 hour, andthe reaction was termination by adding water. The reaction solution wasextracted with dichloromethane, dried over anhydrous magnesium sulfateand concentrated under reduced pressure to obtain the title compound(2.64 g) as a sticky liquid.

Example 144-2: Synthesis of8-chloro-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

2,6-Dichloro-N-(2-hydroxypropyl)-N-[(4-methoxyphenyl)methyl]pyridine-3-carboxamide(2.64 g) obtained in Example 144-1 was dissolved in tetrahydrofuran, and60% sodium hydride (630 mg, 15.8 mmol) was slowly added thereto under anice bath. The reaction solution was slowly heated to room temperature,stirred until the starting material completely disappeared, and methanolwas added to terminate the reaction. To the reaction mixture, saturatedsodium chloride aqueous solution was added, extracted with ethylacetate, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The concentrate was purified by flash chromatographyto obtain the title compound (1.35 g) as a sticky liquid.

Example 144-3: Synthesis of tert-butyl4-[[4-[(4-methoxyphenyl)methyl]-2-methyl-5-oxo-2,3-dihydropyrido[3,2-f][1,4]oxazepin-8-yl]oxy]piperidine-1-carboxylate

The material (500 mg, 1.51 mmol) obtained in Example 144-2, tert-butyl4-hydroxypiperidine-1-carboxylate (460 mg, 2.26 mmol) and 60% sodiumhydride (180 mg, 4.5 mmol) were dissolved in 20 mL of tetrahydrofuranand stirred at 60° C. for one day. The reaction solution was extractedwith saturated aqueous sodium chloride solution and ethyl acetate, andpurified by flash chromatography to obtain the title compound (540 mg).

Example 144-4: Synthesis of2-methyl-8-(4-piperidyloxy)-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one

The material (540 mg) obtained in Example 144-3 was dissolved in 4 mL oftrifluoroacetic acid, and the reaction was carried out by the use of amicrowave at 120° C. for 30 minutes. The reaction solution was dilutedwith ethyl acetate under an ice bath and basified with K₂CO₃ aqueoussolution. The reaction mixture was washed with ethyl acetate 3 times,and KOH was added to the aqueous layer to basify the pH to 9 or higher,followed by extraction with ethyl acetate. The extracted organic layerwas dried over anhydrous sodium sulfate and concentrated to obtain thetitle compound.

Example 144-5: Synthesis of2-methyl-8-[(1-methyl-4-piperidyl)oxy]-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one

The material obtained in Example 144-4 as a starting material was usedin the same manner as in Example 87 to obtain the title compound.

Example 144-6: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

The material obtained in Example 144-5 as a starting material was usedin the same manner as in Example 5 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) (diastereomeric mixture) δ 8.18 (t, J=7.4Hz, 2H), 7.17-7.01 (m, 8H), 6.57 (dd, J=9.0, 3.9 Hz, 2H), 5.10 (s, 2H),4.83 (d, J=7.4 Hz, 3H), 4.29-4.16 (m, 2H), 4.12 (d, J=14.1 Hz, 1H), 3.85(d, J=14.1 Hz, 1H), 3.78-3.66 (m, 8H), 3.68-3.53 (m, 3H), 3.21 (dd,J=13.9, 8.7 Hz, 1H), 2.98-2.85 (m, 9H), 2.85-2.73 (m, 4H), 2.69-2.56 (m,4H), 2.46 (s, 4H), 2.36 (s, 6H), 2.12-2.02 (m, 4H), 1.93-1.78 (m, 4H),1.44 (t, J=6.7 Hz, 6H).

Example 145: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one

The title compound was synthesized in the same manner as in Example 144,except that 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol wasused instead of 1-[(4-methoxyphenyl)methylamino]propan-2-ol.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.0 Hz, 1H), 7.17-7.02 (m,4H), 6.62 (d, J=8.3 Hz, 1H), 5.17-5.03 (m, 1H), 4.32-4.21 (m, 1H), 4.03(d, J=14.1 Hz, 1H), 3.76 (s, 2H), 3.71-3.57 (m, 2H), 3.41 (dd, J=13.8,8.1 Hz, 1H), 2.97-2.84 (m, 4H), 2.85-2.73 (m, 2H), 2.71-2.58 (m, 3H),2.55-2.41 (m, 2H), 2.37 (s, 3H), 2.13-2.01 (m, 2H), 1.91-1.80 (m, 2H),1.45 (d, J=18.4 Hz, 6H).

Example 146: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140 as a starting material was used in the same manner as inExample 141 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.5 Hz, 1H), 7.18-7.04 (m,4H), 6.81 (d, J=8.8 Hz, 1H), 6.58 (d, J=2.8 Hz, 1H), 4.83 (s, 1H), 4.57(s, 1H), 4.32 (d, J=2.0 Hz, 3H), 4.25 (s, 1H), 3.79 (d, J=13.0 Hz, 3H),3.68-3.58 (m, 2H), 3.47 (dd, J=15.6, 9.2 Hz, 1H), 2.92 (d, J=23.0 Hz,5H), 2.70 (d, J=6.3 Hz, 2H), 2.63 (s, 2H), 2.46 (d, J=2.0 Hz, 3H), 2.08(s, 2H), 1.95-1.87 (m, 2H), 1.29 (d, J=6.5 Hz, 3H).

Example 147: Synthesis of4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 147-1: Synthesis of 3,4-dihydro-2H-1,4-benzoxazepin-5-one

Chroman-4-one (2.0 g, 14 mmol) was dissolved in 10 mL of concentratedsulfuric acid, and sodium azide (1.1 g, 18 mmol) was slowly addedthereto at 0° C. The reaction mixture was slowly heated to roomtemperature and stirred for 12 hours. The reaction mixture wasmaintained at 0° C. under an ice bath, and 1 M sodium hydroxide aqueoussolution was slowly added thereto. After basifying the reaction solutionto pH 10 or more, ethyl acetate was added and extracted 3 times. Thecombined organic layers were dried over anhydrous magnesium sulfate, thesolvent was removed by evaporating under reduced pressure, andrecrystallized with dichloromethane and hexane to obtain the titlecompound as a white solid.

Example 147-2: Synthesis of4-(oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

3,4-Dihydro-2H-1,4-benzoxazepin-5-one (163 mg, 1 mmol) obtained inExample 147-1 was dissolved in dimethylformamide, and sodium hydride (52mg, 1.3 mmol) was added thereto under an ice bath. The reaction solutionwas stirred at 0° C. for 30 minutes, and epibromohydrin (0.1 mL, 1.2mmol) was slowly added thereto and stirred at room temperature for 2hours. Methanol was added to the reaction mixture to terminate thereaction, and ethyl acetate was added, and washed with a saturatedaqueous ammonium chloride solution and a saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate. The solvent was removed by evaporating under reduced pressure,and the obtained title compound was used in the next reaction withoutadditional purification.

Example 147-3: Synthesis of4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-(Oxyran-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one obtained inExample 147-2 was dissolved in isopropanol, and tetrahydroisoquinoline(0.13 mL, 1.0 mmol) was added thereto and stirred at 80° C. for 12hours. The temperature was lowered to room temperature temperature, andthe oily liquid obtained by concentrating the solvent was purified byflash chromatography to obtain the transparent and sticky solidcompound. NMR data about the obtained title compound are as follows.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (dd, J=7.9, 1.7 Hz, 1H), 7.48 (td,J=7.8, 1.7 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.15-6.99 (m, 5H), 4.46 (t,J=5.2 Hz, 2H), 4.29-4.18 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.68(td, J=5.1, 1.6 Hz, 2H), 3.44 (dd, J=13.8, 7.7 Hz, 1H), 2.92 (d, J=5.6Hz, 2H), 2.86 (t, J=6.2 Hz, 2H), 2.70-2.59 (m, 2H).

Example 148: Synthesis of2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

Tetralin-1-one (1.9 g, 14 mmol) as a starting material was used in thesame manner as in Example 147 to obtain the title compound, except that35% hydrochloric acid aqueous solution (30 mL) was used instead ofconcentrated sulfuric acid in Example 147-1.

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (d, J=7.9 Hz, 1H), 7.45 (t, J=7.4Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.17-7.02 (m,4H), 4.25 (dt, J=7.8, 3.7 Hz, 1H), 3.95 (dd, J=13.8, 3.7 Hz, 1H),3.48-3.36 (m, 3H), 2.94 (d, J=5.5 Hz, 3H), 2.91-2.86 (m, 2H), 2.82 (t,J=7.1 Hz, 2H), 2.66 (h, J=7.6 Hz, 2H), 2.14 (p, J=6.8 Hz, 2H).

Example 149: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 149-1: Synthesis of4-[[(2R)-oxyran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one

3,4-Dihydro-2H-1,4-benzoxazepin-5-one (163 mg, 1 mmol) obtained inExample 147-1 was dissolved in 5 mL of dimethylformamide, and sodiumhydride (48 mg, 1.2 mmol) was added thereto under an ice bath. Thereaction solution was stirred at 0° C. for 30 minutes, and(R)-(−)-glycidyl nosylate (298 mg, 1.15 mmol) was slowly added theretoand stirred at room temperature for 2 hours. Methanol was added to thereaction mixture to terminate the reaction, and ethyl acetate was added,and washed with a saturated aqueous ammonium chloride solution and asaturated aqueous sodium chloride solution. The organic layer was driedover anhydrous magnesium sulfate. The solvent was removed by evaporatingunder reduced pressure, and the obtained title compound was used in thenext reaction without additional purification.

Example 149-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[[(2R)-oxyran-2-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one obtainedin Example 149-1 was used in the same manner as in Example 147-3 toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (dd, J=7.9, 1.7 Hz, 1H), 7.48 (td,J=7.8, 1.8 Hz, 1H), 7.20 (t, J=7.5 Hz, 1H), 7.15-7.02 (m, 5H), 4.46 (t,J=5.2 Hz, 2H), 4.29-4.19 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H), 3.75(d, J=2.2 Hz, 2H), 3.74-3.63 (m, 2H), 3.44 (dd, J=13.9, 7.7 Hz, 1H),2.97-2.90 (m, 2H), 2.91-2.83 (m, 2H), 2.70-2.60 (m, 2H).

Example 150: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one

7-Fluorochroman-4-one as a starting material was used in the same manneras in Examples 147-1 and 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81-7.73 (m, 1H), 7.16-7.02 (m, 4H),6.94 (td, J=8.5, 2.6 Hz, 1H), 6.81 (dd, J=9.9, 2.6 Hz, 1H), 4.52 (t,J=5.0 Hz, 2H), 4.27-4.20 (m, 1H), 3.99 (dd, J=13.9, 3.6 Hz, 1H),3.81-3.71 (m, 4H), 3.44 (dd, J=13.9, 7.8 Hz, 1H), 2.98-2.84 (m, 4H),2.69-2.61 (m, 2H).

Example 151: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

7-Bromochroman-4-one as a starting material was used in the same manneras in Examples 147-1 and 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.4 Hz, 1H), 7.35 (dd, J=8.4,1.7 Hz, 1H), 7.26 (d, J=1.6 Hz, 1H), 7.16-7.01 (m, 4H), 4.51 (t, J=5.0Hz, 2H), 4.27-4.17 (m, 1H), 3.99 (dd, J=13.7, 3.5 Hz, 1H), 3.74 (d,J=6.5 Hz, 4H), 3.44 (dd, J=13.9, 7.8 Hz, 1H), 2.97-2.83 (m, 4H),2.69-2.59 (m, 2H).

Example 152: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f][1,4]oxazepin-5-one

Example 152-1: Synthesis of methyl3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylate

Methyl 3-hydroxypyridine-4-carboxylate (1.0 g, 6.53 mmol), benzylN-(2-hydroxyethyl)carbamate (1.53 g, 7.84 mmol) and triphenylphosphine(2.06 g) were dissolved in tetrahydrofuran, and diisopropylazodicarboxylate was slowly added thereto at 0° C. The reaction solutionwas stirred at room temperature for 12 hours, and the solvent wasremoved under reduced pressure. The concentrate was purified by flashchromatography under the solvent condition of hexane and ethyl acetateto obtain the title compound.

Example 152-2: Synthesis of3,4-dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one

Methyl 3-[2-(benzyloxycarbonylamino)ethoxy]pyridine-4-carboxylateobtained in Example 152-1 was dissolved in ethanol at room temperature,and 5% palladium-charcoal was added thereto, followed by stirring undera hydrogen balloon for 24 hours. The reaction solution was filteredthrough celite and washed with ethanol. The obtained solution wasconcentrated under reduced pressure and purified by flash chromatographyto obtain the title compound (548 mg) as a white crystalline solid.

Example 152-3: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f][1,4]oxazepin-5-one

3,4-Dihydro-2H-pyrido[4,3-f][1,4]oxazepin-5-one obtained in Example152-2 as a starting material was used in the same manner as in Example149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.36 (s, 1H), 8.31 (d, J=5.1 Hz, 1H),7.75 (d, J=5.1 Hz, 1H), 7.17-7.02 (m, 4H), 4.62 (t, J=4.7 Hz, 2H),4.30-4.20 (m, 1H), 4.02 (dd, J=13.9, 3.5 Hz, 1H), 3.82 (t, J=4.6 Hz,2H), 3.76 (s, 2H), 3.45 (dd, J=13.9, 8.0 Hz, 1H), 2.98-2.90 (m, 2H),2.91-2.83 (m, 2H), 2.69-2.60 (m, 2H).

Example 153: Synthesis of8-chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

8-Chloro-3,4-dihydro-2H-pyrido[3,2-f][1,4]oxazepin-5-one as a startingmaterial was used in the same manner as in Example 149 to obtain thetitle compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.36 (dd, J=8.1, 1.4 Hz, 1H), 7.26 (dd,J=8.2, 1.4 Hz, 1H), 7.17-7.00 (m, 4H), 4.70-4.67 (m, 2H), 4.24 (q,J=9.0, 8.0 Hz, 1H), 3.99 (dd, J=13.9, 3.5 Hz, 1H), 3.89 (t, J=4.3 Hz,2H), 3.76 (s, 2H), 3.42 (dd, J=13.8, 8.1 Hz, 1H), 2.94-2.86 (dd, J=17.3,5.4 Hz, 4H), 2.65 (d, J=6.3 Hz, 2H).

Example 154: Synthesis of7-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

7-Chloro-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting materialwas used in the same manner as in Example 149 to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55 (d, J=8.2 Hz, 1H), 7.35 (dd, J=8.3,1.9 Hz, 1H), 7.27 (d, J=2.1 Hz, 1H), 7.15-7.00 (m, 4H), 4.27-4.18 (m,1H), 3.91 (dd, J=13.8, 3.6 Hz, 1H), 3.75 (s, 2H), 3.44-3.33 (m, 2H),3.32-3.23 (m, 1H), 2.97-2.89 (m, 2H), 2.90-2.82 (m, 2H), 2.78 (t, J=7.1Hz, 2H), 2.68-2.59 (m, 2H), 2.11 (p, J=6.8 Hz, 2H).

Example 155: Synthesis of7-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one

7-Bromo-2,3,4,5-tetrahydro-2-benzazepin-1-one as a starting material wasused in the same manner as in Example 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55-7.51 (m, 1H), 7.51-7.45 (m, 2H),7.16-7.01 (m, 4H), 4.29-4.19 (m, 1H), 3.92 (dd, J=13.8, 3.6 Hz, 1H),3.78 (s, 2H), 3.47-3.38 (m, 2H), 3.36-3.34 (m, 1H), 2.99-2.91 (m, 2H),2.93-2.85 (m, 2H), 2.80 (t, J=7.1 Hz, 2H), 2.71-2.61 (m, 2H), 2.14 (p,J=6.9 Hz, 2H).

Example 156: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

Example 156-1: Synthesis of8-bromo-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione

7-Bromo-1H-3,1-benzoxazine-2,4-dione (550 g, 2.27 mol) was dissolved in2.5 L of distilled water, and triethylamine (230 g, 2.27 mol) andglycine (239 g, 3.18 mol) were added thereto. The reaction solution wasstirred at room temperature for 4 hours, concentrated, dissolved againin 3 L of acetic acid, and the mixture was stirred at 140° C. for 8hours. The reaction solution was diluted with petroleum ether andfiltered to obtain the title compound (866 g, 74.7%) as a white solid.

Example 156-2: Synthesis of8-bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one

8-Bromo-3,4-dihydro-1H-1,4-benzodiazepin-2,5-dione (200 g, 784 mmol)obtained in Example 156-1 was dissolved in 4 L of tetrahydrofuran, andLAH (50.6 g, 1.33 mol) was slowly added thereto at 0° C. The reactionsolution was stirred at 70° C. for 3 hours, and after cooling, 100 mL ofdistilled water, 100 mL of 15% sodium hydroxide aqueous solution, andadditional 100 mL of distilled water were slowly added to terminate thereaction. The mixture solution was dried over anhydrous sodium sulfate,filtered with hot tetrahydrofuran, the solvent was removed under reducedpressure, and recrystallized by adding 500 mL of ethyl acetate to obtainthe title compound (177 g, 46.8%) as a white solid.

Example 156-3: Synthesis of8-bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (177 g, 734 mmol)obtained in Example 156-2 was dissolved in 1.2 L of methanol, andparaformaldehyde (200 g, 3.67 mol) dissolved in 1.2 L of acetic acid wasadded thereto. The reaction solution was stirred at 50° C. for 1 hour.Sodium cyanoborohydride (231 g, 3.67 mol) was added to the reactionsolution, stirred at 50° C. for 4 hours, and concentrated by removingthe solvent under reduced pressure. The mixture was diluted with 4 L ofdistilled water and extracted with dichloromethane 2 times. The combinedorganic layers were washed with saturated aqueous sodium chloridesolution 2 times, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. Methanol was added to the obtainedconcentrate and recrystallized to obtain the title compound (yield: 78%)as a white solid.

Example 156-4: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one

8-Bromo-1-methyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one obtained inExample 156-3 as a starting material was used in the same manner as inExample 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.42 (d, J=7.7 Hz, 1H), 7.20-7.02 (m,6H), 4.23 (m, 1H), 3.94 (dd, J=13.8, 3.9 Hz, 1H), 3.76 (s, 2H), 3.63 (q,J=4.9 Hz, 2H), 3.52-3.37 (m, 3H), 2.93 (d, J=5.7 Hz, 2H), 2.92-2.80 (m,5H), 2.73-2.59 (m, 2H).

Example 157: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one

Example 157-1: Synthesis of8-bromo-1-ethyl-3,4-dihydro-2H-1,4-benzodiazepin-5-one

8-Bromo-1,2,3,4-tetrahydro-1,4-benzodiazepin-5-one (100 mg, 0.41 mmol)obtained in Example 156-2 and potassium carbonate (170 mg, 1.23 mmol)were dissolved in dimethylformamide, and iodoethane (0.07 mL, 0.82 mmol)was added thereto. The reaction solution was stirred at 60° C. for oneday. The reaction mixture was cooled to room temperature, diluted withdistilled water and extracted with ethyl acetate 3 times. The combinedorganic layers were washed with saturated aqueous sodium chloridesolution 2 times, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The obtained concentrate waspurified by flash chromatography to obtain the solid title compound.

Example 157-2: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one

The material obtained in Example 157-1 as a starting material was usedin the same manner as in Example 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.42 (d, J=8.6 Hz, 1H), 7.17-7.09 (m,5H), 7.06 (d, J=5.6 Hz, 1H), 4.23 (dt, J=12.4, 6.4 Hz, 1H), 3.90 (dd,J=13.8, 4.0 Hz, 1H), 3.79 (s, 2H), 3.61 (d, J=5.9 Hz, 2H), 3.49 (dd,J=14.4, 6.8 Hz, 2H), 3.41 (t, J=5.4 Hz, 2H), 3.22 (dt, J=11.9, 6.8 Hz,2H), 2.95-2.88 (m, 4H), 2.76-2.63 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).

Example 158: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1,4-benzodiazepin-2,5-dione

Example 158-1: Synthesis of8-bromo-1-ethyl-3,4-dihydro-1,4-benzodiazepin-2,5-dione

7-Bromo-1-ethyl-3,1-benzoxazine-2,4-dione (262 mg, 0.97 mmol) andglycine (73 mg, 0.97 mmol) were dissolved in acetic acid, and heated toreflux for 4 hours. The reaction mixture was cooled to room temperature,diluted with distilled water and filtered. The obtained solid was washedwith diethyl ether to obtain the solid title compound (100 mg) withoutadditional purification.

Example 158-2: Synthesis of8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1,4-benzodiazepin-2,5-dione

The material obtained in Example 158-1 as a starting material was usedin the same manner as in Example 149 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.72-7.69 (m, 2H), 7.55 (d, J=8.5 Hz,1H), 7.17-6.99 (m, 4H), 4.24 (p, J=7.4 Hz, 2H), 4.15 (dd, J=14.9, 6.0Hz, 1H), 4.01-3.95 (m, 2H), 3.85-3.67 (m, 4H), 3.53-3.45 (m, 1H),2.93-2.86 (m, 4H), 2.63 (d, J=7.0 Hz, 2H), 1.19-1.09 (m, 3H).

Example 159: Synthesis of2-[4-[[4-(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-1-piperidyl]acetonitrile

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 was dissolved in acetonitrile,potassium carbonate and 2-bromoacetonitrile were added thereto, followedby stirring at 90° C. for 1 hour. To the reaction mixture, saturatedaqueous ammonium chloride aqueous solution was added and extracted withethyl acetate 3 times. The oily liquid obtained by drying the combinedorganic layers over anhydrous sodium sulfate and concentrating underreduced pressure was purified by flash chromatography to obtain thetitle compound as a white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (dd, J=8.7, 2.2 Hz, 1H), 7.16-7.09(m, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.81 (dd, J=8.8, 2.7 Hz, 1H), 6.64 (d,J=2.6 Hz, 1H), 4.76 (dq, J=7.2, 3.8 Hz, 1H), 4.47 (d, J=5.4 Hz, 2H),4.23 (s, 1H), 4.17-4.07 (m, 1H), 3.97 (dt, J=13.8, 3.2 Hz, 1H),3.86-3.65 (m, 6H), 3.61 (t, J=11.6 Hz, 1H), 3.43 (dd, J=14.2, 7.6 Hz,1H), 2.97-2.86 (m, 4H), 2.67 (d, J=6.1 Hz, 2H), 2.04 (t, J=6.5 Hz, 3H),1.87 (ddd, J=23.5, 11.9, 4.2 Hz, 2H), 1.26 (td, J=7.4, 2.2 Hz, 1H).

Example 160: Synthesis of8-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 78except that difluoro-acetic anhydride was used instead of aceticanhydride in Example 78-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (dd, J=8.8, 2.1 Hz, 1H), 7.14 (h,J=5.8 Hz, 3H), 7.07 (d, J=7.0 Hz, 1H), 6.77 (dd, J=8.8, 2.9 Hz, 1H),6.60 (d, J=2.3 Hz, 1H), 4.52 (s, 1H), 4.47 (d, J=5.4 Hz, 2H), 4.26 (s,1H), 3.95 (dd, J=13.9, 3.4 Hz, 1H), 3.86 (s, 2H), 3.77-3.65 (m, 4H),3.46 (dd, J=14.0, 7.5 Hz, 1H), 2.98 (s, 3H), 2.88-2.67 (m, 4H), 2.58 (t,J=9.5 Hz, 2H), 2.08-2.00 (m, 2H), 1.86 (d, J=11.8 Hz, 2H).

Example 161: Synthesis of8-[[1-(2,2-difluoroacetyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 83-1 as a starting material was usedin the same manner as in Example 160 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.72 (dd, J=8.7, 2.0 Hz, 1H), 7.14 (d,J=5.7 Hz, 3H), 7.07 (d, J=6.9 Hz, 1H), 6.69 (d, J=8.6 Hz, 1H), 6.49 (d,J=2.3 Hz, 1H), 5.21-5.14 (m, 1H), 4.88-4.77 (m, 1H), 4.60-4.37 (m, 4H),4.25 (d, J=7.2 Hz, 1H), 4.11 (td, J=11.8, 10.3, 5.3 Hz, 2H), 3.96 (dd,J=13.9, 3.2 Hz, 1H), 3.85 (s, 2H), 3.72 (h, J=7.3, 6.4 Hz, 2H), 3.46(dd, J=14.1, 7.6 Hz, 1H), 2.97 (s, 3H), 2.80-2.69 (m, 2H).

Example 162: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride (100 mg, 0.19 mmol) obtained in Example 78-1, potassiumcarbonate (79 mg, 0.57 mmol) and 2-iodoethanol (15 μL, 0.19 mmol) weredissolved in acetonitrile and stirred. After completion of the reaction,the reaction solution was concentrated and purified by flashchromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.9 Hz, 1H), 7.11-7.03 (m,4H), 6.76 (d, J=8.9 Hz, 1H), 6.59 (s, 1H), 4.51-4.46 (m, 3H), 4.18 (s,1H), 3.98 (d, J=13.9 Hz, 1H), 3.76-3.71 (m, 6H), 3.42 (dd, J=14.0, 7.9Hz, 1H), 3.02-2.79 (m, 6H), 2.71-2.58 (m, 4H), 2.58-2.43 (m, 2H), 2.04(t, J=7.4 Hz, 2H), 1.91-1.75 (m, 2H).

Example 163: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 162except that 2-fluoroethyl 4-methylbenzenesulfonate was used instead of2-iodoethanol at 90° C.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.7 Hz, 1H), 7.17-7.01 (m,4H), 6.76 (d, J=8.9 Hz, 1H), 6.58 (s, 1H), 4.66 (t, J=5.0 Hz, 1H),4.59-4.42 (m, 4H), 4.23 (s, 1H), 3.97 (d, J=13.4 Hz, 1H), 3.84-3.66 (m,4H), 3.42 (dd, J=13.9, 7.6 Hz, 1H), 3.02-2.76 (m, 7H), 2.75-2.59 (m,3H), 2.51 (t, J=10.2 Hz, 2H), 2.13-2.00 (m, 2H), 1.93-1.75 (m, 2H).

Example 164: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-onedihydrochloride as a starting material was used in the same manner as inExample 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.26 (d, J=8.5 Hz, 1H), 7.19-6.97 (m,4H), 6.55 (d, J=8.5 Hz, 1H), 5.08 (s, 1H), 4.66 (s, 1H), 4.61 (s, 2H),4.55 (s, 1H), 4.29-4.18 (m, 1H), 3.99 (d, J=13.9 Hz, 1H), 3.90-3.83 (m,2H), 3.75 (s, 2H), 3.43-3.37 (m, 1H), 2.99-2.83 (m, 6H), 2.80 (s, 1H),2.73 (s, 1H), 2.63 (d, J=6.2 Hz, 2H), 2.55-2.43 (m, 2H), 2.14-2.03 (m,2H), 1.90-1.77 (m, 2H).

Example 165: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[[1-[(3-methyloxetan-3-yl)methyl]-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one(200 mg, 0.443 mmol) obtained in Example 78-1, cesium carbonate (288 mg,0.886 mmol) and 3-(bromomethyl)-3-methyl-oxetan (110 mg, 0.665 mmol)were dissolved in dimethylformamide, heated to 60° C. and stirred. Aftercompletion of the reaction, the reaction solution was extracted withsaturated aqueous sodium chloride solution and ethyl acetate, andpurified by flash chromatography to obtain the title compound (6 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.7 Hz, 1H), 7.12 (d, J=3.1Hz, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 6.57 (d, J=3.2Hz, 1H), 4.56-4.46 (m, 4H), 4.45 (s, 2H), 4.33 (d, J=5.7 Hz, 2H), 4.23(s, 1H), 4.01-3.92 (m, 1H), 3.80-3.69 (m, 4H), 3.42 (dd, J=14.0, 7.6 Hz,1H), 2.97-2.85 (m, 4H), 2.66 (d, J=6.7 Hz, 2H), 2.61 (s, 3H), 2.31 (t,J=10.3 Hz, 2H), 2.06-1.98 (m, 2H), 1.79 (t, J=10.2 Hz, 2H), 1.43 (s,3H).

Example 166: Synthesis of4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoazepin-8-yl]oxy]piperidine-1-carbonitrile

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one(200 mg, 0.443 mmol) obtained in Example 78-1, cyanogen bromide (94 mg,0.886 mmol) and cesium carbonate (433 mg, 1.329 mmol) were dissolved indimethylformamide, and the reaction was carried out by the use of amicrowave at 70° C. for 3 hours. After completion of the reaction, thereaction solution was extracted with saturated aqueous sodium chloridesolution and ethyl acetate, and purified by flash chromatography toobtain the title compound (14 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (dd, J=8.7, 2.1 Hz, 1H), 7.14-7.09(m, 3H), 7.05 (d, J=6.7 Hz, 1H), 6.79 (dd, J=8.8, 2.3 Hz, 1H), 6.63 (d,J=2.4 Hz, 1H), 4.65 (dq, J=7.1, 3.6 Hz, 1H), 4.51-4.43 (m, 2H), 4.23 (d,J=7.3 Hz, 1H), 3.97 (dt, J=14.1, 2.9 Hz, 1H), 3.82-3.69 (m, 4H),3.55-3.37 (m, 3H), 3.26 (t, J=9.9 Hz, 2H), 2.93 (d, J=5.6 Hz, 2H),2.91-2.84 (m, 2H), 2.65 (d, J=6.3 Hz, 2H), 2.09 (t, J=10.7 Hz, 2H),1.94-1.81 (m, 2H).

Example 167: Synthesis of8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Example 167-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(piperazin-1-ylmethyl)-3H-1,4-benzoxazepin-5-one;dihydrochloride

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one as a starting material was used in the samemanner as in Examples 54-1 and 54-2 to obtain the title compound.

Example 167-2: Synthesis of8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

The material obtained in Example 167-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=7.8 Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.17-7.02 (m, 4H), 7.00 (s, 1H), 4.29 (s, 1H), 4.06 (d, J=13.6Hz, 1H), 3.77 (s, 2H), 3.59 (t, J=10.1 Hz, 6H), 3.48 (s, 2H), 3.43 (dd,J=14.0, 8.0 Hz, 2H), 2.93 (s, 4H), 2.74-2.56 (m, 2H), 2.55-2.41 (m, 4H),2.10 (s, 3H), 1.43 (s, 3H), 1.33 (s, 3H).

Example 168: Synthesis of3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carbaldehyde

Example 168-1: Synthesis of8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-onedi hydrochloride

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,2-dimethyl-3H-1,4-benzoxazepin-5-oneas a starting material was used in the same manner as in Example 83-1 toobtain the title compound.

Example 168-2: Synthesis of3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidine-1-carbaldehyde

The material (105 mg, 0.2 mmol) obtained in Example 168-1 was dissolvedin 2 mL of acetonitrile, and formic acid (38 μL, 1.0 mmol),triethylamine (0.17 mL, 1.2 mL) and HATU (114 mg, 0.3 mmol) were addedthereto and stirred at room temperature.

After confirming that the reaction was complete, saturated aqueousammonium chloride solution was added and extracted with ethyl acetate 3times. The combined organic layers were dried over anhydrous magnesiumsulfate, concentrated under reduced pressure and purified by flashchromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.03 (s, 1H), 7.62 (d, J=8.4 Hz, 1H),7.21-7.03 (m, 4H), 6.72 (d, J=8.7 Hz, 1H), 6.45 (s, 1H), 5.19 (s, 1H),4.68 (t, J=8.4 Hz, 1H), 4.52-4.42 (m, 1H), 4.35-4.18 (m, 2H), 4.02 (t,J=13.6 Hz, 2H), 3.79 (s, 2H), 3.51 (s, 2H), 3.43-3.37 (m, 1H), 2.93 (d,J=11.6 Hz, 4H), 2.73-2.59 (m, 2H), 1.44 (s, 3H), 1.35 (s, 3H).

Example 169: Synthesis of4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]methyl]piperazine-1-carbaldehyde

The material obtained in Example 167-1 as a starting material was usedin the same manner as in Example 168-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.03 (s, 1H), 7.61 (d, J=7.9 Hz, 1H),7.23 (d, J=8.0 Hz, 1H), 7.19-7.03 (m, 4H), 7.01 (s, 1H), 4.30 (s, 1H),4.06 (d, J=13.8 Hz, 1H), 3.79 (s, 2H), 3.61 (s, 2H), 3.56 (s, 2H),3.52-3.38 (m, 5H), 2.93 (d, J=11.0 Hz, 4H), 2.75-2.60 (m, 2H), 2.49 (d,J=17.2 Hz, 4H), 1.44 (s, 3H), 1.34 (s, 3H).

Example 170: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one as a starting material was used in the samemanner as in Example 28 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=7.8 Hz, 1H), 7.19-7.01 (m,5H), 6.92 (s, 1H), 4.76 (s, 4H), 4.29 (s, 1H), 4.06 (d, J=13.8 Hz, 1H),3.76 (s, 2H), 3.62 (s, 2H), 3.47 (s, 6H), 3.43-3.38 (m, 1H), 2.98-2.83(m, 4H), 2.64 (s, 2H), 1.43 (s, 3H), 1.33 (s, 3H).

Example 171: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 171-1: Synthesis of8-[(8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

The intermediate was synthesized by changing 4-chlorotetrahydropyran totert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octan-8-carboxylate inExample 64. The obtained intermediate as a starting material was used inthe same manner as in Example 78-1 to obtain the title compound.

Example 171-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 171-1 as a starting material was usedin the same manner as in Example 88 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=8.7 Hz, 1H), 7.09-6.92 (m,4H), 6.61 (d, J=8.8 Hz, 1H), 6.42 (s, 1H), 4.56 (d, J=5.1 Hz, 1H), 4.38(d, J=5.3 Hz, 2H), 4.13 (d, J=7.5 Hz, 1H), 4.00-3.87 (m, 1H), 3.65 (d,J=6.7 Hz, 4H), 3.42-3.27 (m, 3H), 2.96-2.71 (m, 4H), 2.53 (dd, J=14.6,6.8 Hz, 4H), 2.09 (dd, J=29.8, 11.7 Hz, 4H), 2.01-1.78 (m, 4H), 1.09 (t,J=7.3 Hz, 3H).

Example 172: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 172-1: Synthesis of8-(2-azaspiro[3.3]heptan-6-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate was synthesized by changing 4-chlorotetrahydropyran totert-butyl 6-methylsulfonyloxy-2-azaspiro[3.3]heptan-2-carboxylate inExample 64. The obtained intermediate as a starting material was used inthe same manner as in Example 78-1 to obtain the title compound.

Example 172-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[3.3]heptan-6-yloxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 172-1 as a starting material was usedin the same manner as in Example 88 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.65 (dd, J=8.7, 2.1 Hz, 1H), 7.18-6.99(m, 4H), 6.65 (d, J=8.5 Hz, 1H), 6.44 (d, J=3.0 Hz, 1H), 4.66 (t, J=6.8Hz, 1H), 4.45 (d, J=5.1 Hz, 2H), 4.33-4.18 (m, 1H), 3.97 (dt, J=14.1,2.9 Hz, 1H), 3.82-3.70 (m, 4H), 3.45-3.28 (m, 7H), 2.92 (d, J=5.8 Hz,2H), 2.87 (d, J=6.0 Hz, 2H), 2.73 (ddd, J=11.3, 7.0, 3.6 Hz, 2H), 2.63(d, J=6.3 Hz, 2H), 2.58-2.48 (m, 2H), 2.26 (ddd, J=13.1, 6.2, 2.4 Hz,2H), 0.99 (td, J=7.3, 2.0 Hz, 3H).

Example 173: Synthesis of8-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(8-Azabicyclo[3.2.1]octan-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 171-1 as a starting material wasused in the same manner as in Example 78-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (dd, J=8.8, 2.0 Hz, 1H), 7.19-6.99(m, 4H), 6.71 (dd, J=8.8, 2.6 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.92 (s,2H), 4.73 (d, J=4.9 Hz, 1H), 4.65-4.55 (m, 1H), 4.46 (d, J=5.1 Hz, 2H),4.32-4.17 (m, 2H), 3.97 (dd, J=13.9, 3.4 Hz, 1H), 3.80-3.67 (m, 4H),3.41 (dd, J=14.1, 7.6 Hz, 1H), 3.01-2.81 (m, 4H), 2.64 (d, J=6.2 Hz,2H), 2.32-1.91 (m, 9H).

Example 174: Synthesis of8-[(2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(2-Azaspiro[3.3]heptan-6-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 172-1 as a starting material wasused in the same manner as in Example 78-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.54 (dd, J=8.9, 2.3 Hz, 1H), 7.12-6.87(m, 4H), 6.53 (dd, J=7.2, 4.3 Hz, 1H), 6.35 (d, J=2.7 Hz, 1H), 4.57 (q,J=6.6 Hz, 1H), 4.33 (d, J=5.1 Hz, 2H), 4.23-4.04 (m, 3H), 3.93 (s, 1H),3.84 (d, J=11.1 Hz, 2H), 3.75-3.51 (m, 4H), 3.36-3.26 (m, 1H), 2.89-2.72(m, 4H), 2.67 (ddt, J=13.7, 6.7, 3.1 Hz, 2H), 2.61-2.46 (m, 2H), 2.22(ddd, J=10.2, 6.6, 3.2 Hz, 2H), 1.74 (dd, J=6.7, 2.3 Hz, 3H).

Example 175: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

Example 175-1: Synthesis of methyl

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(1.0 equiv), molybdenum hexacarbonyl (1.0 equiv),trans-bis(acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II)(0.1 equiv), tri-tert-butylphosphonium tetrafluoroborate (0.2 equiv) and1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 equiv) were dissolved inmethanol:acetonitrile (=1:1) and stirred at 150° C. for 3 hours. Thereaction solution was cooled to room temperature, diluted with ethylacetate and filtered through celite. The filtrate was concentrated underreduced pressure, distilled water was added, and the mixture wasextracted with ethyl acetate 3 times. The combined organic layers weredried over anhydrous magnesium sulfate, concentrated and purified byflash chromatography to obtain the title compound.

Example 175-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

Methyl4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-carboxylate(1.0 equiv) obtained in Example 175-1, pyrrolidine (5.0 equiv) and1,8-diazabicyclo[5.4.0]undec-7-ene (1 mL) were mixed and heated to 120°C. overnight. The reaction mixture was extracted with ethyl acetate,dried over magnesium sulfate and purified by flash chromatography toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (dd, J=8.1, 2.2 Hz, 1H), 7.19 (d,J=8.0 Hz, 1H), 7.06 (s, 1H), 7.04-6.85 (m, 4H), 4.39 (t, J=5.2 Hz, 2H),4.12 (dt, J=11.3, 4.9 Hz, 1H), 3.88 (dt, J=13.9, 3.1 Hz, 1H), 3.63 (d,J=11.4 Hz, 4H), 3.48 (t, J=7.1 Hz, 2H), 3.34 (q, J=7.3 Hz, 3H),2.90-2.65 (m, 4H), 2.54 (d, J=5.9 Hz, 2H), 1.84 (dp, J=33.2, 6.7 Hz,4H).

Example 176: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that piperidine was used instead of pyrrolidine in Example 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.07 (d, J=8.1Hz, 1H), 6.97 (d, J=20.8 Hz, 5H), 4.41 (d, J=5.3 Hz, 2H), 4.13 (s, 1H),3.88 (d, J=13.9 Hz, 1H), 3.74-3.53 (m, 6H), 3.35 (dd, J=14.0, 7.8 Hz,1H), 2.79 (dd, J=18.3, 5.6 Hz, 4H), 2.54 (d, J=6.3 Hz, 2H), 1.75-1.49(m, 5H).

Example 177: Synthesis of8-(3,3-difluoropyrrolidin-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that 3,3-difluoropyrrolidine was used instead of pyrrolidine inExample 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.80 (d, J=7.8 Hz, 1H), 7.22 (d, J=8.1Hz, 1H), 7.12 (q, J=11.5, 8.0 Hz, 5H), 4.54 (d, J=5.4 Hz, 2H), 4.27 (s,1H), 4.05-3.95 (m, 1H), 3.89-3.72 (m, 5H), 3.64-3.39 (m, 4H), 2.96 (s,4H), 2.72 (d, J=6.7 Hz, 2H), 2.56 (s, 2H), 2.44 (s, 2H), 2.35 (d, J=2.1Hz, 3H).

Example 178: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that 1-methylpiperazine was used instead of pyrrolidine inExample 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (dd, J=8.0, 2.2 Hz, 1H), 7.22 (t,J=6.7 Hz, 1H), 7.10 (s, 1H), 7.08-6.88 (m, 4H), 4.40 (d, J=5.5 Hz, 2H),4.13 (s, 1H), 3.95-3.70 (m, 4H), 3.63 (d, J=7.8 Hz, 5H), 3.35 (dd,J=14.1, 7.8 Hz, 1H), 2.81 (d, J=5.7 Hz, 2H), 2.76 (t, J=5.7 Hz, 2H),2.54 (d, J=6.1 Hz, 2H), 2.45-2.25 (m, 2H).

Example 179: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrrolidin-1-ylmethyl)-3H-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one as a starting material was used in the samemanner as in Example 24 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=7.9 Hz, 1H), 7.23 (d, J=8.0Hz, 1H), 7.17-7.03 (m, 4H), 7.01 (s, 1H), 4.29 (s, 1H), 4.06 (d, J=13.5Hz, 1H), 3.76 (s, 2H), 3.72 (s, 2H), 3.49 (s, 2H), 3.43 (dd, J=13.7, 8.2Hz, 1H), 2.98-2.83 (m, 4H), 2.64 (d, J=7.2 Hz, 6H), 1.86 (s, 4H), 1.44(s, 3H), 1.34 (s, 3H).

Example 180: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-1,4-benzoxazepin-5-one dihydrochloride obtained inExample 110-5 as a starting material was used in the same manner as inExample 78-2 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.59 (dd, J=8.7, 2.5 Hz, 1H), 7.15-7.09(m, 3H), 7.06 (d, J=6.4 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 6.57 (s, 1H),4.72 (dd, J=8.6, 4.9 Hz, 1H), 4.29 (s, 1H), 4.04 (d, J=13.8 Hz, 1H),3.90-3.72 (m, 4H), 3.53 (d, J=17.0 Hz, 4H), 3.40 (dd, J=13.9, 8.3 Hz,1H), 2.91 (dd, J=19.8, 5.2 Hz, 4H), 2.67-2.60 (m, 2H), 2.14 (d, J=2.4Hz, 3H), 2.11-1.93 (m, 2H), 1.79 (d, J=31.6 Hz, 2H), 1.43 (s, 3H), 1.34(d, J=2.4 Hz, 3H).

Example 181: Synthesis of4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carbaldehyde

The material obtained in Example 110-5 as a starting material was usedin the same manner as in Example 78 to obtain the title compound, exceptthat formic acid was used instead of acetic anhydride in Example 78-2.

¹H NMR (400 MHz, Methanol-d₄) δ 8.06 (s, 1H), 7.63-7.56 (m, 1H), 7.12(s, 3H), 7.07 (s, 1H), 6.85 (d, J=9.1 Hz, 1H), 6.58 (s, 1H), 4.77 (s,1H), 4.28 (s, 1H), 4.04 (d, J=13.9 Hz, 1H), 3.73 (d, J=32.7 Hz, 5H),3.57-3.37 (m, 6H), 2.89 (s, 2H), 2.64 (d, J=7.3 Hz, 2H), 2.03 (s, 2H),1.77 (s, 2H), 1.43 (s, 3H), 1.33 (d, J=13.9 Hz, 3H).

Example 182: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]-3H-1,4-benzoxazepin-5-one

The material obtained in Example 167-1 as a starting material was usedin the same manner as in Example 92 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.17-7.01 (m, 4H), 6.99 (s, 1H), 4.70 (t, J=6.8 Hz, 2H),4.66-4.53 (m, 2H), 4.29 (s, 1H), 4.06 (d, J=13.9 Hz, 1H), 3.77 (s, 2H),3.59 (s, 2H), 3.53 (t, J=7.0 Hz, 1H), 3.48 (s, 2H), 3.42 (dd, J=13.5,8.3 Hz, 1H), 3.01-2.81 (m, 4H), 2.71-2.27 (m, 10H), 1.43 (s, 3H), 1.33(s, 3H).

Example 183: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-7-azaspiro[3.4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one as a starting material was used in the samemanner as in Example 29 to obtain the title compound, except that2-oxa-7-azaspiro[3.4]octane was used instead of 3-methoxyazetidinehydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.49 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.9Hz, 1H), 7.04-6.90 (m, 4H), 6.86 (s, 1H), 4.51 (p, J=5.7, 5.2 Hz, 4H),4.17 (s, 1H), 3.94 (d, J=13.6 Hz, 1H), 3.64 (s, 2H), 3.53 (s, 2H), 3.36(s, 2H), 3.31 (dd, J=13.9, 8.2 Hz, 2H), 2.85-2.68 (m, 6H), 2.60-2.43 (m,4H), 2.06 (t, J=7.3 Hz, 2H), 1.32 (s, 3H), 1.22 (s, 3H).

Example 184: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that 4-fluoropiperidine was used instead of pyrrolidine inExample 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.80 (dd, J=7.9, 2.2 Hz, 1H), 7.22 (d,J=8.0 Hz, 1H), 7.17-6.97 (m, 5H), 5.00-4.76 (m, 1H), 4.52 (d, J=5.2 Hz,2H), 4.24 (d, J=7.1 Hz, 1H), 4.07-3.83 (m, 2H), 3.76 (d, J=6.6 Hz, 5H),3.63-3.36 (m, 4H), 2.94 (d, J=5.6 Hz, 2H), 2.89 (d, J=5.4 Hz, 2H), 2.67(d, J=6.0 Hz, 2H), 2.13-1.70 (m, 3H).

Example 185: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that 3-trifluoromethylpiperidine was used instead of pyrrolidinein Example 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=7.9 Hz, 1H), 7.10 (d, J=8.1Hz, 1H), 7.05-6.81 (m, 5H), 4.66-4.23 (m, 3H), 4.13 (q, J=6.1, 5.4 Hz,1H), 3.88 (dt, J=14.2, 2.9 Hz, 1H), 3.64 (d, J=6.5 Hz, 5H), 3.34 (dd,J=14.1, 7.8 Hz, 1H), 2.97 (dt, J=45.9, 12.8 Hz, 2H), 2.81 (d, J=5.6 Hz,2H), 2.77 (d, J=5.4 Hz, 2H), 2.54 (d, J=6.3 Hz, 2H), 2.45-2.29 (m, 1H),1.99 (d, J=12.2 Hz, 1H), 1.70-1.37 (m, 3H).

Example 186: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 175,except that 4-trifluoromethylpiperidine was used instead of pyrrolidinein Example 175-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.75-7.61 (m, 1H), 7.09 (d, J=8.0 Hz,1H), 7.05-6.83 (m, 5H), 4.62 (d, J=13.2 Hz, 1H), 4.41 (d, J=5.6 Hz, 2H),4.13 (d, J=6.7 Hz, 1H), 3.88 (dt, J=14.0, 3.1 Hz, 1H), 3.63 (s, 5H),3.34 (dd, J=14.0, 7.7 Hz, 1H), 3.05 (t, J=13.9 Hz, 1H), 2.88-2.67 (m,5H), 2.53 (d, J=6.3 Hz, 2H), 2.47-2.30 (m, 1H), 2.01-1.83 (m, 1H), 1.75(d, J=12.8 Hz, 1H), 1.43 (q, J=13.5, 12.9 Hz, 2H).

Example 187: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

2,6-Dimethylmorpholine (33 μL, 1.1 equiv) was dissolved in 1,4-dioxane(1 mL), and 2 M trimethylaluminum toluene solution (134 μL, 1.1 equiv)was added thereto under the condition of nitrogen at 0° C. The reactionmixture was stirred at room temperature for 1 hour, and methyl4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxylate(100 mg) dissolved in 1,4-dioxane was added thereto. The reactionsolution was stirred at 110° C. for 3 hours, and the reaction wasterminated with a saturated aqueous potassium sodium tartrate solution,followed by extraction with ethyl acetate. The combined organic layerswere dried over anhydrous magnesium sulfate, concentrated and purifiedby flash chromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1Hz, 1H), 7.18-7.00 (m, 5H), 4.63-4.44 (m, 3H), 4.33-4.18 (m, 1H), 4.00(dt, J=13.9, 2.8 Hz, 1H), 3.75 (d, J=7.6 Hz, 4H), 3.71-3.55 (m, 2H),3.55-3.39 (m, 2H), 2.99-2.80 (m, 5H), 2.62 (dd, J=23.2, 9.1 Hz, 3H),1.24 (d, J=6.5 Hz, 3H), 1.09 (dd, J=17.3, 6.2 Hz, 3H).

Example 188: Synthesis of8-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 187,except that 2-azabicyclo[2.2.1]heptane was used instead of2,6-dimethylmorpholine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.86-7.73 (m, 1H), 7.29 (d, J=8.1 Hz,1H), 7.24-6.99 (m, 5H), 4.52 (q, J=6.0 Hz, 2H), 4.24 (dd, J=10.3, 5.4Hz, 1H), 4.12 (s, 1H), 4.00 (dt, J=14.1, 3.2 Hz, 1H), 3.75 (d, J=8.9 Hz,4H), 3.60-3.38 (m, 2H), 3.12 (dd, J=63.7, 10.4 Hz, 1H), 2.99-2.84 (m,4H), 2.76-2.56 (m, 3H), 1.89-1.66 (m, 4H), 1.59 (d, J=9.9 Hz, 1H), 1.52(q, J=10.4, 7.9 Hz, 1H).

Example 189: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 187,except that 3-oxa-8-azabicyclo[3.2.1]octane was used instead of2,6-dimethylmorpholine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (d, J=7.8 Hz, 1H), 7.30 (d, J=8.0Hz, 1H), 7.18 (s, 1H), 7.15-7.02 (m, 4H), 4.64 (s, 1H), 4.53 (d, J=5.3Hz, 2H), 4.29-4.19 (m, 1H), 4.04-3.93 (m, 2H), 3.81 (d, J=11.5 Hz, 1H),3.77-3.66 (m, 6H), 3.59 (d, J=11.1 Hz, 1H), 3.46 (dd, J=14.0, 7.8 Hz,1H), 2.92 (d, J=5.7 Hz, 2H), 2.87 (d, J=5.8 Hz, 2H), 2.65 (d, J=6.2 Hz,2H), 2.05 (dd, J=28.2, 10.9 Hz, 4H).

Example 190: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 187,except that 2-methylmorpholine was used instead of2,6-dimethylmorpholine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (d, J=7.9 Hz, 1H), 7.21 (d, J=8.0Hz, 1H), 7.17-6.92 (m, 5H), 4.62-4.35 (m, 3H), 4.24 (dq, J=11.4, 6.7,6.1 Hz, 1H), 4.08-3.68 (m, 6H), 3.65-3.18 (m, 5H), 2.92 (d, J=5.6 Hz,2H), 2.87 (d, J=5.7 Hz, 2H), 2.66 (t, J=7.1 Hz, 2H), 1.23 (h, J=6.1, 5.0Hz, 2H), 1.06 (d, J=6.2 Hz, 1H).

Example 191: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 187,except that 3-methylmorpholine was used instead of2,6-dimethylmorpholine.

¹H NMR (400 MHz, Methanol-d₄) δ 7.81 (d, J=8.0 Hz, 1H), 7.28-6.97 (m,6H), 4.51 (d, J=5.2 Hz, 2H), 4.24 (q, J=7.3, 6.0 Hz, 1H), 3.99 (dd,J=13.8, 3.3 Hz, 1H), 3.95-3.62 (m, 7H), 3.59-3.39 (m, 3H), 3.06-2.72 (m,4H), 2.67 (d, J=6.1 Hz, 2H), 1.37 (d, J=7.0 Hz, 3H).

Example 192: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-Chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one as a starting material was usedin the same manner as in Example 22 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.14 (d, J=7.9 Hz, 1H), 7.43 (d, J=7.0Hz, 1H), 7.19-7.01 (m, 4H), 4.35-4.21 (m, 1H), 4.05 (d, J=13.8 Hz, 1H),3.77 (s, 2H), 3.73 (s, 4H), 3.62 (s, 4H), 3.45 (dd, J=14.0, 8.6 Hz, 1H),2.92 (s, 2H), 2.89 (s, 2H), 2.66 (q, J=5.7, 4.1 Hz, 2H), 1.50 (s, 3H),1.43 (s, 3H).

Example 193: Synthesis of8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 193-1: Synthesis of potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-carboxylate

Methyl4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-carboxylateand potassium trimethylsilanoate were dissolved in tetrahydrofuran andstirred at room temperature overnight. The reaction solution wasconcentrated under reduced pressure and used in the next reactionwithout additional purification.

Example 193-2: Synthesis of8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The starting material (100 mg, 1.0 equiv) obtained in Example 193-1,octahydrocyclopenta[c]pyrrole (1.5 equiv), HATU (131 mg, 1.5 equiv) anddiisopropylethylamine (120 μL, 3 equiv) were dissolved in methylenechloride and stirred at room temperature for 2 hours. The reactionsolution was extracted with methylene chloride, dried over magnesiumsulfate and purified by flash chromatography to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (dd, J=8.0, 2.1 Hz, 1H), 7.16 (d,J=8.0 Hz, 1H), 7.08-6.89 (m, 5H), 4.41 (q, J=5.7 Hz, 2H), 4.13 (dd,J=9.8, 5.2 Hz, 1H), 3.88 (dt, J=14.2, 3.1 Hz, 1H), 3.75-3.60 (m, 5H),3.55 (dd, J=11.4, 7.9 Hz, 1H), 3.43-3.34 (m, 2H), 3.21 (d, J=2.8 Hz,2H), 3.18-3.07 (m, 1H), 2.89-2.73 (m, 4H), 2.73-2.46 (m, 4H), 1.73 (ddt,J=39.4, 20.0, 7.0 Hz, 3H), 1.49 (ddt, J=33.3, 12.5, 6.8 Hz, 2H), 1.28(dt, J=11.8, 5.8 Hz, 1H).

Example 194: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 193,except that 3-fluoropiperidine was used instead ofoctahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=7.8 Hz, 1H), 7.08 (d, J=8.0Hz, 1H), 7.06-6.89 (m, 5H), 4.57 (d, J=48.2 Hz, 1H), 4.41 (t, J=5.1 Hz,2H), 4.33-4.08 (m, 2H), 3.89 (dd, J=13.8, 3.2 Hz, 1H), 3.64 (d, J=7.0Hz, 5H), 3.52-3.23 (m, 3H), 3.17-2.95 (m, 1H), 2.90-2.71 (m, 4H), 2.54(d, J=6.2 Hz, 2H), 1.89-1.65 (m, 2H), 1.50 (d, J=50.2 Hz, 1H).

Example 195: Synthesis of8-(2,2-difluoromorpholin-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 193,except that 2,2-difluoromorpholine was used instead ofoctahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=7.6 Hz, 1H), 7.13 (d, J=8.0Hz, 1H), 7.08-6.89 (m, 5H), 4.41 (d, J=5.3 Hz, 2H), 4.14 (d, J=6.5 Hz,1H), 4.08-3.77 (m, 5H), 3.71-3.42 (m, 6H), 3.36 (dd, J=14.1, 7.7 Hz,1H), 3.23 (d, J=16.0 Hz, 2H), 2.87-2.74 (m, 4H), 2.56 (d, J=6.1 Hz, 2H).

Example 196: Synthesis of8-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 193,except that 4,4-difluoropiperidine was used instead ofoctahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (dd, J=8.0, 2.2 Hz, 1H), 7.13 (d,J=8.0 Hz, 1H), 7.06-6.91 (m, 5H), 4.46-4.34 (m, 2H), 4.14 (dd, J=7.2,3.9 Hz, 1H), 3.85 (dt, J=14.0, 3.2 Hz, 1H), 3.75 (s, 1H), 3.70 (s, 2H),3.62 (s, 2H), 3.42 (m, 3H), 2.93-2.78 (m, 4H), 2.59 (d, J=5.9 Hz, 2H),2.12-1.78 (m, 4H).

Example 197: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-piperidylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-Chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one as a starting material was usedin the same manner as in Example 23 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.13 (d, J=7.7 Hz, 1H), 7.42 (d, J=7.8Hz, 1H), 7.19-7.01 (m, 4H), 4.29 (s, 1H), 4.06 (d, J=13.7 Hz, 1H), 3.75(s, 2H), 3.69-3.54 (m, 4H), 3.45 (dd, J=13.7, 8.3 Hz, 1H), 3.00-2.80 (m,4H), 2.72-2.57 (m, 2H), 2.50 (s, 4H), 1.70-1.58 (m, 4H), 1.50 (s, 5H),1.44 (s, 3H).

Example 198: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 198-1: Synthesis of tert-butylN-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]cyclohexyl]-N-methyl-carbamate

The title compound was synthesized in the same manner as in Example 64,except that[4-[tert-butoxycarbonyl(methyl)amino]cyclohexyl]methanesulfonate, cesiumcarbonate and acetonitrile were used instead of 4-chlorotetrahydropyran,potassium carbonate and dimethylformamide, respectively.

Example 198-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

Tert-butylN-[4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]cyclohexyl]-N-methyl-carbamateobtained in Example 198-1 was dissolved in methanol, and 4 Mhydrochloric acid solution dissolved in 1,4-dioxane was slowly addedthereto. The reaction solution was stirred at room temperature, dilutedwith diethyl ether and filtered to obtain the solid title compound.

Example 198-3: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 198-2 as a starting material wasused in the same manner as in Example 87 to obtain the title compound,except that oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.7 Hz, 1H), 7.12 (d, J=3.8Hz, 3H), 7.06 (d, J=6.5 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.58 (s, 1H),4.67 (d, J=7.1 Hz, 4H), 4.61 (s, 1H), 4.46 (d, J=5.5 Hz, 2H), 4.23 (d,J=7.3 Hz, 1H), 4.06 (q, J=7.3 Hz, 1H), 3.97 (dd, J=14.0, 3.6 Hz, 1H),3.78 (s, 2H), 3.73 (d, J=5.4 Hz, 2H), 3.43 (dd, J=14.0, 7.6 Hz, 1H),2.97-2.86 (m, 4H), 2.67 (d, J=6.2 Hz, 2H), 2.47 (t, J=11.2 Hz, 1H), 2.24(s, 3H), 2.12 (d, J=12.0 Hz, 2H), 1.64 (tt, J=23.8, 11.0 Hz, 6H).

Example 199: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl(methyl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-(methylamino)cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride (200 mg, 0.362 mmol) obtained in Example 198-2,potassium carbonate (150 mg, 1.086 mmol) and 2-fluoroethyl4-methylbenzenesulfonate (93 μl, 0.543 mmol) were dissolved inacetonitrile and stirred at 100° C. for one day. To the reactionmixture, saturated aqueous ammonium chloride aqueous solution was addedand extracted with ethyl acetate 3 times. The oily liquid obtained bydrying the combined organic layers over anhydrous sodium sulfate andconcentrating under reduced pressure was purified by flashchromatography to obtain the title compound (45 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (dd, J=8.9, 2.5 Hz, 1H), 7.10 (d,J=3.5 Hz, 3H), 7.04 (d, J=6.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 6.58 (s,1H), 4.61 (q, J=4.0 Hz, 2H), 4.47 (dq, J=12.2, 4.3, 3.9 Hz, 3H), 4.22(dq, J=10.0, 5.8, 5.0 Hz, 1H), 3.97 (dd, J=13.9, 3.1 Hz, 1H), 3.72 (d,J=9.9 Hz, 4H), 3.45-3.35 (m, 1H), 2.86 (td, J=23.1, 4.6 Hz, 6H),2.69-2.50 (m, 3H), 2.37 (d, J=2.5 Hz, 3H), 2.12 (d, J=12.8 Hz, 2H),1.75-1.56 (m, 6H).

Example 200: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4-piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Example 200-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydrO-1,4-benzoxazepin-5-onedi hydrochloride

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 78-1 to obtain the title compound.

Example 200-2: Synthesis of8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 200-1 as a starting material was usedin the same manner as in Example 78-2 to obtain the title compound

Example 200-3: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4-piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 200-2 as a starting material wasdissolved in tetrahydrofuran, and Lawesson's reagent was added thereto.The reaction mixture was stirred at 50° C. until the reaction wascompleted, the reaction solution was cooled to room temperature,distilled water was added, and the mixture was extracted with ethylacetate. The combined organic layers were dried over anhydrous magnesiumsulfate, concentrated and purified by flash chromatography to obtain thetitle compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.19-8.09 (m, 1H), 7.65-7.55 (m, 1H),7.29 (d, J=9.3 Hz, 2H), 6.89 (dd, J=32.8, 8.6 Hz, 3H), 5.46 (s, 1H),4.80 (s, 1H), 4.65 (s, 1H), 4.44 (s, 2H), 4.18-4.07 (m, 2H), 3.99 (s,1H), 3.83 (d, J=2.4 Hz, 5H), 3.60-3.45 (m, 1H), 2.67 (s, 2H), 2.14-2.00(m, 3H), 1.95-1.80 (m, 2H), 1.35-1.20 (m, 3H), 1.03 (d, J=6.3 Hz, 2H).

Example 201: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)azetidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Example 201-1: Synthesis of8-(azetidin-3-yloxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in the same manner as in Examples 140-1 to 140-5except that[(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate wasused instead of[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as astarting material and the method in the same manner as in Example 64except that tert-butyl 3-hydroxyazetidine-1-carboxylate is used insteadof 4-chlorotetrahydropyran. The obtained intermediate was dissolved inmethanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxanewas added thereto. The reaction solution was stirred at room temperatureuntil the reaction was terminated, diluted with ethyldiethyl ether andfiltered to obtain the title compound as a white solid in the form ofdihydrochloride.

Example 201-2: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)azetidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained in Example 201-1 as a starting material,2-fluoroethyl para-toluenesulfonate and potassium carbonate weredissolved in acetonitrile, and the reaction solution was stirred at 60°C. for one day. The reaction mixture was cooled to room temperature,diluted with distilled water, and extracted with ethyl acetate 3 times.The combined organic layers were washed twice with a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate,filtered and concentrated under reduced pressure. The obtainedconcentrate was purified by flash chromatography to obtain the solidtitle compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (dd, J=8.7, 2.5 Hz, 1H), 7.12 (d,J=3.7 Hz, 3H), 7.06 (d, J=6.6 Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 6.43 (d,J=3.2 Hz, 1H), 4.82 (ddd, J=10.1, 6.6, 3.4 Hz, 1H), 4.55 (q, J=3.9 Hz,1H), 4.43 (q, J=3.9 Hz, 1H), 4.25 (td, J=6.8, 3.6 Hz, 1H), 3.90 (t,J=7.4 Hz, 2H), 3.80 (d, J=14.0 Hz, 3H), 3.62 (dt, J=15.2, 3.4 Hz, 2H),3.46 (ddd, J=15.0, 9.8, 5.3 Hz, 1H), 2.90 (tdd, J=20.0, 9.1, 4.9 Hz,7H), 2.68 (dd, J=6.4, 2.4 Hz, 2H), 1.38-1.25 (m, 4H).

Example 202: Synthesis of(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)-4-piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1R)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140 as a starting material was used in the same manner as inExample 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (dd, J=8.6, 2.1 Hz, 1H), 7.12 (d,J=3.2 Hz, 3H), 7.06 (d, J=6.5 Hz, 1H), 6.79 (d, J=8.7 Hz, 1H), 6.55 (s,1H), 4.67 (s, 1H), 4.58-4.49 (m, 2H), 4.24 (s, 1H), 3.78 (d, J=8.0 Hz,2H), 3.67-3.58 (m, 2H), 3.47 (dd, J=15.6, 9.3 Hz, 1H), 2.93 (d, J=5.4Hz, 2H), 2.91-2.81 (m, 4H), 2.80 (s, 1H), 2.73 (t, J=5.2 Hz, 1H), 2.66(d, J=6.4 Hz, 2H), 2.52 (t, J=10.2 Hz, 2H), 2.05 (d, J=10.5 Hz, 2H),1.85 (s, 2H), 1.31-1.26 (m, 3H).

Example 203: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-3H-1,4-benzoxazepin-5-one

Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylateas a starting material was used in the same manner as in Example 193 toobtain the title compound, except that 3-oxa-8-azabicyclo[3.2.1]octanewas used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=7.9 Hz, 1H), 7.28-7.15 (m,1H), 7.06-6.88 (m, 5H), 4.53 (s, 1H), 4.26-4.08 (m, 1H), 3.98-3.92 (m,1H), 3.84 (s, 1H), 3.70 (d, J=11.0 Hz, 1H), 3.61 (d, J=26.9 Hz, 4H),3.48 (d, J=11.0 Hz, 1H), 3.39 (s, 2H), 3.32 (dd, J=13.7, 8.3 Hz, 1H),2.84-2.72 (m, 4H), 2.58-2.48 (m, 2H), 1.33 (s, 3H), 1.23 (s, 3H).

Example 204: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one

Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylateas a starting material was used in the same manner as in Example 193 toobtain the title compound, except that 2-oxa-5-azabicyclo[2.2.1]heptanewas used instead of octahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67-7.55 (m, 1H), 7.30-7.16 (m, 1H),7.07-6.86 (m, 5H), 4.24-4.10 (m, 1H), 4.02-3.89 (m, 1H), 3.85 (dd,J=7.7, 3.4 Hz, 1H), 3.71 (ddd, J=31.5, 7.7, 1.6 Hz, 1H), 3.64 (s, 2H),3.53-3.42 (m, 1H), 3.42-3.35 (m, 3H), 3.32 (td, J=6.5, 4.9, 2.5 Hz, 1H),2.84-2.69 (m, 4H), 2.58-2.45 (m, 2H), 1.95-1.72 (m, 2H), 1.40-1.27 (m,3H), 1.27-1.17 (m, 3H).

Example 205: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,5-dimethylmorpholin-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepine-8-carboxylateas a starting material was used in the same manner as in Example 193 toobtain the title compound, except that 3,5-dimethylmorpholine was usedinstead of octahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.58 (d, J=7.8 Hz, 1H), 7.13 (dd, J=7.8,1.6 Hz, 1H), 7.05-6.91 (m, 4H), 6.89 (d, J=1.6 Hz, 1H), 4.16 (q, J=7.9,6.8 Hz, 1H), 3.94 (dd, J=13.7, 3.7 Hz, 1H), 3.69-3.51 (m, 4H), 3.45-3.25(m, 7H), 2.80 (d, J=5.7 Hz, 2H), 2.77-2.71 (m, 2H), 2.52 (dd, J=6.3, 3.8Hz, 2H), 1.40 (s, 6H), 1.32 (s, 3H), 1.22 (s, 3H).

Example 206: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 206-1: Synthesis of tert-butyl

4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylate

The title compound was synthesized in the same manner as in Example 64,except that tert-butyl3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate, cesium carbonateand acetonitrile were used instead of 4-chlorotetrahydropyran, potassiumcarbonate and dimethylformamide, respectively.

Example 206-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

Tert-butyl4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]-3-fluoro-piperidine-1-carboxylateobtained in Example 206-1 was dissolved in methanol, and 4 Mhydrochloric acid solution dissolved in 1,4-dioxane was slowly addedthereto. The reaction solution was stirred at room temperature, dilutedwith diethyl ether and filtered to obtain the solid title compound.

Example 206-3: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained inExample 206-2 as a starting material was used in the same manner as inExample 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.18-7.06 (m,3H), 7.06-7.01 (m, 1H), 6.82 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=2.5 Hz,1H), 4.79-4.43 (m, 4H), 4.29-4.18 (m, 1H), 3.98 (dd, J=13.9, 3.6 Hz,1H), 3.78-3.64 (m, 4H), 3.42 (dd, J=13.9, 7.7 Hz, 1H), 3.07-2.83 (m,5H), 2.74-2.58 (m, 3H), 2.51 (q, J=8.2, 7.7 Hz, 1H), 2.36 (s, 4H),2.24-2.15 (m, 1H), 1.77 (dtd, J=13.1, 9.0, 3.7 Hz, 1H).

Example 207: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained inExample 206-2 as a starting material was used in the same manner as inExample 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.17-7.02 (m,4H), 6.82 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 4.65 (dq,J=5.6, 4.6 Hz, 2H), 4.56-4.45 (m, 4H), 4.27-4.17 (m, 1H), 3.98 (dd,J=13.9, 3.6 Hz, 1H), 3.81-3.69 (m, 4H), 3.43 (dd, J=13.9, 7.7 Hz, 1H),2.94 (d, J=5.4 Hz, 2H), 2.90-2.83 (m, 4H), 2.79 (dt, J=9.4, 5.0 Hz, 2H),2.76-2.71 (m, 1H), 2.68-2.62 (m, 2H), 2.53 (dd, J=11.2, 7.5 Hz, 1H),2.47-2.38 (m, 1H), 2.21 (dd, J=9.7, 4.6 Hz, 1H), 1.76 (dd, J=11.9, 7.8Hz, 1H).

Example 208: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(3-fluoro-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one dihydrochloride obtained inExample 206-2 as a starting material was used in the same manner as inExample 162 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.17-7.00 (m,4H), 6.81 (dd, J=8.8, 2.5 Hz, 1H), 6.65 (d, J=2.5 Hz, 1H), 4.67 (dtd,J=49.2, 8.2, 4.6 Hz, 1H), 4.48 (t, J=5.0 Hz, 3H), 4.23 (s, 1H), 3.98(dd, J=13.9, 3.6 Hz, 1H), 3.82-3.62 (m, 6H), 3.43 (dd, J=13.9, 7.6 Hz,1H), 3.26-3.14 (m, 1H), 2.98-2.80 (m, 5H), 2.71-2.56 (m, 4H), 2.47 (q,J=8.9, 8.3 Hz, 1H), 2.37 (t, J=10.4 Hz, 1H), 2.26-2.14 (m, 1H),1.80-1.65 (m, 1H).

Example 209: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-carboxylateas a starting material was used in the same manner as in Example 193 toobtain the title compound, except that1,2,3,4-tetrahydropyrrol[1,2-a]pyrazine was used instead ofoctahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.75 (d, J=7.9 Hz, 1H), 7.31 (d, J=7.9Hz, 1H), 7.21-6.96 (m, 5H), 6.65 (s, 1H), 6.08 (d, J=16.4 Hz, 1H), 5.85(d, J=81.0 Hz, 1H), 4.87 (s, 1H), 4.62 (s, 1H), 4.32 (tt, J=8.5, 4.3 Hz,1H), 4.20-3.96 (m, 4H), 3.79 (d, J=20.8 Hz, 3H), 3.56-3.40 (m, 3H), 2.95(q, J=5.0, 4.2 Hz, 4H), 2.70 (t, J=5.6 Hz, 2H), 1.45 (s, 3H), 1.36 (s,3H).

Example 210: Synthesis of8-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one

Potassium;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-carboxylateas a starting material was used in the same manner as in Example 193 toobtain the title compound, except that1,2,3,4,6,7,8,8a-octahydropyrrol[1,2-a]pyrazine was used instead ofoctahydrocyclopenta[c]pyrrole in Example 193-2.

¹H NMR (400 MHz, Methanol-d₄ δ 7.73 (d, J=7.8 Hz, 1H), 7.26 (dd, J=7.8,1.6 Hz, 1H), 7.18-6.96 (m, 5H), 4.70 (dd, J=50.1, 13.0 Hz, 1H), 4.30(dd, J=7.5, 3.6 Hz, 1H), 4.07 (d, J=14.6 Hz, 1H), 3.79 (s, 3H), 3.52 (s,2H), 3.44 (dd, J=13.8, 8.4 Hz, 1H), 3.33 (p, J=1.7 Hz, 4H), 3.23-3.05(m, 2H), 2.98 (d, J=12.7 Hz, 1H), 2.75-2.63 (m, 2H), 2.25 (q, J=12.1,11.3 Hz, 2H), 2.13-1.98 (m, 2H), 1.88 (dd, J=48.6, 16.4 Hz, 4H),1.62-1.51 (m, 1H), 1.45 (s, 3H), 1.35 (s, 3H).

Example 211: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin-2-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2,3-dihydro-1,4-benzoxazepin-5-one(1.0 equiv), 2-chloro-5-fluoropyrimidine (1.5 equiv) and cesiumcarbonate (2 equiv) were dissolved in acetonitrile and heated to refluxovernight. The reaction solution was extracted with ethyl acetate. Theseparated organic layer was dried over magnesium sulfate, concentratedand purified by flash chromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.46 (s, 2H), 7.67 (d, J=8.6 Hz, 1H),7.08-6.92 (m, 4H), 6.89 (dd, J=8.6, 2.4 Hz, 1H), 6.77 (d, J=2.3 Hz, 1H),4.39 (t, J=5.0 Hz, 2H), 4.14 (tt, J=7.6, 3.6 Hz, 1H), 3.87 (dd, J=13.9,3.6 Hz, 1H), 3.70 (d, J=2.3 Hz, 2H), 3.65 (t, J=5.1 Hz, 2H), 3.35 (dd,J=13.9, 7.6 Hz, 1H), 2.87-2.75 (m, J=4.4, 3.8 Hz, 4H), 2.62-2.54 (m,2H).

Example 212: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 was dissolved in a mixturesolution of water and acetonitrile, and 2-methoxirane and sodiumhydroxide were added thereto and stirred at room temperature for 1 hour.To the reaction mixture, water was added and extracted with ethylacetate 3 times. The oily liquid obtained by drying the combined organiclayers over anhydrous sodium sulfate and concentrating under reducedpressure was purified by flash chromatography to obtain the titlecompound as a white solid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.17-6.97 (m,4H), 6.76 (dd, J=8.8, 2.5 Hz, 1H), 6.59 (d, J=2.5 Hz, 1H), 4.49 (dt,J=18.2, 4.4 Hz, 3H), 4.23 (t, J=5.4 Hz, 1H), 4.04-3.91 (m, 2H),3.83-3.67 (m, 4H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 3.00-2.83 (m, 6H),2.69-2.41 (m, 6H), 2.05 (d, J=14.9 Hz, 2H), 1.93-1.78 (m, 2H), 1.18 (d,J=6.2 Hz, 3H).

Example 213: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 213-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The title compound was synthesized in the same manner as in Examples 64and 78-1, except that tert-butyl(S)-3-methylsulfonyloxypiperidine-1-carboxylate was used instead of4-chlorotetrahydropyran in Example 64.

Example 213-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 213-1 as a starting material wasused in the same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.60 (d, J=8.8 Hz, 1H), 7.12-6.92 (m,4H), 6.70 (dd, J=8.8, 2.5 Hz, 1H), 6.53 (d, J=2.5 Hz, 1H), 4.40 (t,J=5.0 Hz, 3H), 4.15 (q, J=7.1, 5.2 Hz, 1H), 3.90 (dd, J=13.9, 3.6 Hz,1H), 3.76-3.53 (m, 4H), 3.36 (dd, J=13.9, 7.6 Hz, 1H), 2.92-2.72 (m,5H), 2.63-2.45 (m, 3H), 2.28 (s, 4H), 2.04-1.76 (m, 3H), 1.58 (d, J=20.6Hz, 2H).

Example 214: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propanoyl-2,3-dihydro-1,4-benzoxazepin-5-one

Example 214-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-N-methoxy-N-methyl-5-oxo-2,3-dihydro-1,4-benzoxazepine-8-carboxamide

The title compound was synthesized in the same manner as in Example193-2, except that N,O-dimethylhydroxyamine hydrochloride was usedinstead of octahydrocyclopenta[c]pyrrole.

Example 214-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propanoyl-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-N-methoxy-N-methyl-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-carboxamate(700 mg, 1 equiv) was dissolved in tetrahydrofuran, and 1 Methylmagnesium bromide (2 mL, tetrahydrofuran solution) was addedthereto at 0° C. The reaction solution was stirred at room temperaturefor 5 hours, extracted with ethyl acetate, dried over magnesium sulfateand purified by flash chromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.74-7.59 (m, 2H), 7.50 (d, J=1.6 Hz,1H), 7.05-6.86 (m, 4H), 4.40 (t, J=5.1 Hz, 2H), 4.12 (tdd, J=7.5, 5.4,3.6 Hz, 1H), 3.88 (dd, J=13.8, 3.6 Hz, 1H), 3.70-3.61 (m, 2H), 3.60 (dt,J=5.0, 2.5 Hz, 2H), 3.40-3.30 (m, 1H), 2.94 (q, J=7.2 Hz, 2H), 2.89-2.69(m, 4H), 2.58-2.52 (m, 2H), 1.07 (t, J=7.2 Hz, 3H).

Example 215: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 215-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

The intermediate was synthesized by changing 4-chlorotetrahydropyran totert-butyl 3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylatein Example 64. The obtained intermediate was dissolved in methanol, and4 N hydrochloric acid solution dissolved in 1,4-dioxane was addedthereto. The mixture was stirred at room temperature until the reactionwas completed, diluted with ethyl diethyl ether and filtered to obtainthe title compound as a white solid in the form of divalentdihydrochloride.

Example 215-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 215-1 as a starting material wasused in the same manner as in Example 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.18-6.99 (m,4H), 6.69 (dd, J=8.8, 2.5 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.65 (dt,J=9.8, 5.0 Hz, 2H), 4.54 (t, J=5.0 Hz, 1H), 4.47 (t, J=5.0 Hz, 2H), 4.24(d, J=5.7 Hz, 1H), 3.98 (dd, J=13.9, 3.7 Hz, 1H), 3.74 (dd, J=11.1, 6.0Hz, 4H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 3.36 (s, 2H), 2.88 (ddd, J=26.4,14.4, 5.1 Hz, 5H), 2.76 (t, J=5.0 Hz, 1H), 2.69-2.60 (m, 2H), 2.23 (d,J=15.2 Hz, 2H), 2.16-1.98 (m, 4H), 1.98-1.90 (m, 2H).

Example 216: Synthesis of8-(cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 241,except that cyclopropylmagnesium bromide was used instead ofethylmagnesium bromide in Example 214-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=1.1 Hz, 2H), 7.54 (d, J=1.1Hz, 1H), 7.07-6.80 (m, 4H), 4.39 (t, J=5.1 Hz, 2H), 4.17-4.06 (m, 1H),3.87 (dd, J=13.8, 3.6 Hz, 1H), 3.69-3.51 (m, 4H), 3.33 (dd, J=13.8, 7.7Hz, 1H), 2.80 (t, J=6.2 Hz, 2H), 2.73 (dd, J=8.8, 3.7 Hz, 2H), 2.71-2.66(m, 1H), 2.59-2.45 (m, 2H), 1.07-0.92 (m, 4H).

Example 217: Synthesis of8-(cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 241,except that cyclopentylmagnesium bromide was used instead ofethylmagnesium bromide in Example 214-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.75-7.60 (m, 2H), 7.51 (d, J=1.5 Hz,1H), 7.04-6.88 (m, 4H), 4.41 (t, J=5.1 Hz, 2H), 4.13 (tdd, J=7.5, 5.3,3.5 Hz, 1H), 3.88 (dd, J=13.9, 3.6 Hz, 1H), 3.75-3.58 (m, 5H), 3.36 (dd,J=13.9, 7.7 Hz, 1H), 2.87-2.70 (m, 4H), 2.61-2.49 (m, 2H), 1.86 (dtdd,J=10.2, 7.6, 6.0, 2.9 Hz, 2H), 1.74 (dq, J=13.3, 7.2 Hz, 2H), 1.66-1.51(m, 4H).

Example 218: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that [rac-(3R)-1-methyl-3-piperidyl]methanesulfonate was usedinstead of 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.18-7.00 (m,4H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 4.49 (dt,J=14.9, 4.4 Hz, 3H), 4.27-4.18 (m, 1H), 3.98 (dd, J=13.9, 3.6 Hz, 1H),3.81-3.68 (m, 4H), 3.42 (dd, J=13.9, 7.7 Hz, 1H), 2.94 (t, J=6.2 Hz,2H), 2.90-2.79 (m, 3H), 2.68-2.54 (m, 3H), 2.33 (s, 4H), 2.08-1.80 (m,3H), 1.73-1.53 (m, 2H).

Example 219: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 162 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.18-7.02 (m,4H), 6.80 (dd, J=8.7, 2.5 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.79 (dt,J=7.2, 3.6 Hz, 1H), 4.56 (s, 1H), 4.30-4.20 (m, 1H), 4.15 (dd, J=13.7,3.7 Hz, 1H), 3.84-3.70 (m, 3H), 3.64 (dd, J=15.5, 3.4 Hz, 1H), 3.50 (dd,J=15.5, 7.7 Hz, 1H), 3.26-3.18 (m, 2H), 2.93 (dd, J=15.1, 4.1 Hz, 5H),2.79-2.58 (m, 5H), 2.08 (d, J=9.8 Hz, 2H), 1.89 (s, 2H), 1.32 (s, 3H).

Example 220: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140 as a starting material was used in the same manner as inExample 212 to obtain the title compound, except that2,2-dimethyloxirane was used instead of 2-methoxirane.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=8.7 Hz, 1H), 7.17-7.02 (m,4H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.84-4.74 (m,1H), 4.44 (dt, J=8.0, 4.1 Hz, 1H), 4.29-4.19 (m, 1H), 4.15 (dd, J=13.7,3.6 Hz, 1H), 3.78 (d, J=11.8 Hz, 2H), 3.63 (dd, J=15.6, 3.4 Hz, 1H),3.49 (dd, J=15.6, 7.6 Hz, 1H), 3.23 (dd, J=13.8, 8.2 Hz, 1H), 2.91 (dt,J=19.8, 5.5 Hz, 6H), 2.68-2.50 (m, 4H), 2.38 (s, 2H), 2.08-1.97 (m, 2H),1.85-1.75 (m, 2H), 1.32 (dd, J=7.0, 3.1 Hz, 2H), 1.21 (s, 6H).

Example 221: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

Example 221-1: Synthesis of8-acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example214-2, except that methylmagnesium bromide was used instead ofethylmagnesium bromide.

Example 221-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

8-Acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 1 equiv), morpholine (66 μL, 3 equiv), sodium cyanoborohydride(48 mg, 3 equiv) and acetic acid (1 drop) were dissolved in 1 mL ofmethanol and stirred at 80° C. for 6 hours. The reaction mixture wasextracted with ethyl acetate, dried over magnesium sulfate and purifiedby flash chromatography to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.0,1.5 Hz, 1H), 7.03-6.95 (m, 3H), 6.92 (d, J=7.2 Hz, 2H), 4.35 (t, J=5.1Hz, 2H), 4.11 (dt, J=9.6, 3.5 Hz, 1H), 3.86 (dd, J=13.9, 3.6 Hz, 1H),3.63 (s, 2H), 3.57 (dt, J=9.6, 4.8 Hz, 6H), 3.31 (dd, J=13.8, 7.6 Hz,1H), 3.23 (s, 1H), 2.81 (t, J=6.1 Hz, 2H), 2.74 (t, J=5.7 Hz, 2H),2.60-2.48 (m, 2H), 2.48-2.33 (m, 2H), 2.25 (dt, J=10.9, 4.7 Hz, 2H),1.24 (d, J=6.6 Hz, 3H).

Example 222: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 221,except that 2-oxa-6-azaspiro[3.3]heptane was used instead of morpholinein Example 221-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.56 (d, J=8.0 Hz, 1H), 7.05-6.91 (m,5H), 6.88 (d, J=1.6 Hz, 1H), 4.61 (s, 4H), 4.35 (t, J=5.1 Hz, 2H),4.18-4.04 (m, 1H), 3.85 (dd, J=13.9, 3.6 Hz, 1H), 3.65 (d, J=2.0 Hz,2H), 3.62-3.50 (m, 2H), 3.35-3.16 (m, 6H), 2.89-2.69 (m, 4H), 2.62-2.47(m, 2H), 1.10 (d, J=6.5 Hz, 3H).

Example 223: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-pynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 1.0 equiv), prop-2-yn-1-ol (3 equiv),bis(triphenylphosphine)palladium (II) dichloride (8 mg, 0.05 equiv),copper (I) iodide (5 mg, 0.1 equiv) and triethylamine (97 μL, 3 equiv)were dissolved in N,N-dimethylformamide (1 mL) and stirred at 100° C.for 4 hours. The reaction solution was cooled to room temperature,filtered through celite and extracted with saturated aqueous ammoniumchloride solution and ethyl acetate. The combined organic layers werewashed with saturated aqueous sodium chloride solution and dried overmagnesium sulfate. The obtained solution was concentrated under reducedpressure and purified by flash chromatography to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.1 Hz, 1H), 7.23 (dd, J=8.1,1.6 Hz, 1H), 7.19-6.99 (m, 5H), 4.48 (t, J=5.1 Hz, 2H), 4.42 (s, 2H),4.31-4.18 (m, 1H), 3.98 (dd, J=13.9, 3.6 Hz, 1H), 3.82-3.76 (m, 2H),3.76-3.68 (m, 2H), 3.45 (dd, J=13.9, 7.6 Hz, 1H), 3.01-2.82 (m, 4H),2.73-2.62 (m, 2H).

Example 224: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 163 to obtain the title compound, except that1-bromo-2-methoxyethane was used instead of 2-fluoroethylpara-toluenesulfonate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.17-7.02 (m,4H), 6.78 (dd, J=8.7, 2.5 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.79 (td,J=7.0, 3.3 Hz, 1H), 4.50 (t, J=3.7 Hz, 1H), 4.23 (dt, J=8.6, 4.0 Hz,1H), 4.15 (dd, J=13.8, 3.7 Hz, 1H), 3.77 (s, 2H), 3.68-3.45 (m, 4H),3.37 (s, 2H), 3.23 (dd, J=13.8, 8.2 Hz, 1H), 2.94 (d, J=5.3 Hz, 2H),2.88 (t, J=5.5 Hz, 4H), 2.66 (dt, J=13.4, 6.6 Hz, 4H), 2.50 (d, J=10.2Hz, 2H), 2.10-2.00 (m, 2H), 1.88-1.80 (m, 2H), 1.35-1.30 (m, 3H).

Example 225: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 4-pyridylboronic acid was used instead of isobutylboronicacid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.70-8.56 (m, 2H), 7.87 (d, J=8.1 Hz,1H), 7.81-7.69 (m, 2H), 7.60 (dd, J=8.2, 1.8 Hz, 1H), 7.48 (d, J=1.8 Hz,1H), 7.17-7.04 (m, 4H), 4.56 (t, J=5.0 Hz, 2H), 4.27 (d, J=5.4 Hz, 1H),4.03 (dd, J=13.9, 3.6 Hz, 1H), 3.79 (d, J=7.0 Hz, 4H), 3.48 (dd, J=13.9,7.7 Hz, 1H), 2.95 (d, J=5.2 Hz, 2H), 2.89 (dd, J=8.9, 3.5 Hz, 2H), 2.68(dd, J=6.2, 2.1 Hz, 2H).

Example 226: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(4-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 223,except that 4-ethynylpyridine was used instead of prop-2-yn-1-ol.

¹H NMR (400 MHz, Methanol-d₄) δ 8.55-8.33 (m, 2H), 7.63 (d, J=8.0 Hz,1H), 7.50-7.40 (m, 2H), 7.26 (dd, J=8.1, 1.6 Hz, 1H), 7.14 (d, J=1.6 Hz,1H), 7.09-6.83 (m, 4H), 4.39 (t, J=5.1 Hz, 2H), 4.13 (dddd, J=9.0, 7.4,4.6, 2.6 Hz, 1H), 3.87 (dd, J=13.9, 3.6 Hz, 1H), 3.70-3.52 (m, 4H), 3.35(dd, J=13.8, 7.7 Hz, 1H), 2.88-2.69 (m, 4H), 2.65-2.48 (m, 2H).

Example 227: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(3-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 223,except that 3-ethynylpyridine was used instead of prop-2-yn-1-ol.

¹H NMR (400 MHz, Methanol-d₄) δ 8.67-8.56 (m, 1H), 8.43 (dd, J=5.0, 1.6Hz, 1H), 7.88 (dt, J=8.0, 1.9 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.36(ddd, J=8.0, 5.0, 0.9 Hz, 1H), 7.25 (dd, J=8.1, 1.6 Hz, 1H), 7.13 (d,J=1.5 Hz, 1H), 7.06-6.96 (m, 3H), 6.95-6.89 (m, 1H), 4.39 (t, J=5.1 Hz,2H), 4.11 (ddd, J=7.4, 5.7, 3.4 Hz, 1H), 3.88 (dd, J=13.9, 3.5 Hz, 1H),3.70-3.52 (m, 4H), 3.32 (dd, J=13.8, 7.8 Hz, 1H), 2.82 (t, J=6.2 Hz,2H), 2.75 (t, J=5.5 Hz, 2H), 2.57-2.40 (m, 2H).

Example 228: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybu-1-tynyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 223,except that but-3-yn-2-ol was used instead of prop-2-yn-1-ol.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.0 Hz, 1H), 7.21 (dd, J=8.1,1.6 Hz, 1H), 7.16-6.94 (m, 5H), 4.70 (q, J=6.6 Hz, 1H), 4.47 (t, J=5.1Hz, 2H), 4.22 (dq, J=10.1, 5.6, 4.5 Hz, 1H), 3.98 (dd, J=13.9, 3.5 Hz,1H), 3.75 (s, 2H), 3.73-3.64 (m, 2H), 3.43 (dd, J=13.9, 7.7 Hz, 1H),2.92 (d, J=5.6 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H), 2.64 (d, J=6.5 Hz, 2H),1.50 (d, J=6.6 Hz, 3H).

Example 229: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)pro-1-pynyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 223,except that N-methylprop-2-yn-1-amine was used instead ofprop-2-yn-1-ol.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55 (d, J=8.1 Hz, 1H), 7.11 (dd, J=8.1,1.6 Hz, 1H), 7.06-6.89 (m, 5H), 4.36 (t, J=5.1 Hz, 2H), 4.18-4.05 (m,1H), 3.86 (dd, J=13.9, 3.6 Hz, 1H), 3.68-3.63 (m, 2H), 3.59 (dt, J=5.0,2.9 Hz, 2H), 3.52 (s, 2H), 3.33 (dd, J=13.9, 7.7 Hz, 1H), 2.81 (d, J=5.3Hz, 2H), 2.75 (dd, J=8.9, 3.6 Hz, 2H), 2.57-2.50 (m, 2H), 2.39 (s, 3H).

Example 230: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 3-pyridylboronic acid was used instead of isobutylboronicacid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.94-8.83 (m, 1H), 8.64-8.53 (m, 1H),8.21-8.09 (m, 1H), 7.85 (d, J=8.1 Hz, 1H), 7.64-7.46 (m, 2H), 7.40 (d,J=1.8 Hz, 1H), 7.18-6.92 (m, 4H), 4.56 (t, J=5.1 Hz, 2H), 4.31-4.23 (m,1H), 4.03 (dd, J=13.8, 3.6 Hz, 1H), 3.84-3.75 (m, 4H), 3.49 (dd, J=13.9,7.7 Hz, 1H), 3.00-2.87 (m, 4H), 2.70 (dd, J=6.3, 2.4 Hz, 2H).

Example 231: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 1,3-dimethylpyrazoleboronic acid was used instead ofisobutylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.84 (s, 1H), 7.73 (d, J=8.1 Hz, 1H),7.28 (dd, J=8.1, 1.8 Hz, 1H), 7.18-7.03 (m, 5H), 4.51 (t, J=5.1 Hz, 2H),4.30-4.22 (m, 1H), 4.00 (dd, J=13.8, 3.6 Hz, 1H), 3.88 (s, 3H),3.83-3.72 (m, 4H), 3.47 (dd, J=13.9, 7.6 Hz, 1H), 2.93 (ddd, J=11.9,9.3, 4.3 Hz, 4H), 2.74-2.62 (m, 2H), 2.40 (s, 3H).

Example 232: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 1-methylpyrazoleboronic acid was used instead ofisobutylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.06 (s, 1H), 7.93-7.81 (m, 1H),7.74-7.66 (m, 1H), 7.39 (dd, J=8.1, 1.7 Hz, 1H), 7.25 (d, J=1.7 Hz, 1H),7.16-7.02 (m, 4H), 4.50 (t, J=5.1 Hz, 2H), 4.31-4.21 (m, 1H), 4.03-3.89(m, 4H), 3.81 (s, 2H), 3.78-3.71 (m, 2H), 3.47 (dd, J=13.9, 7.6 Hz, 1H),2.94 (dd, J=9.5, 4.6 Hz, 4H), 2.72-2.66 (m, 2H).

Example 233: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 1,5-dimethylpyrazoleboronic acid was used instead ofisobutylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.83-7.53 (m, 3H), 7.25 (dd, J=8.1, 1.7Hz, 1H), 7.11 (ddd, J=14.4, 6.0, 2.5 Hz, 4H), 4.52 (t, J=5.1 Hz, 2H),4.27 (d, J=9.2 Hz, 1H), 4.01 (dd, J=13.9, 3.7 Hz, 1H), 3.86 (s, 3H),3.82-3.71 (m, 4H), 3.48 (dd, J=13.9, 7.6 Hz, 1H), 2.93 (dt, J=8.6, 4.9Hz, 4H), 2.73-2.64 (m, 2H), 2.46 (s, 3H).

Example 234: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-pyrido[3,2-f][1,4]oxazepin-5-onedihydrochloride as a starting material was used in the same manner as inExample 162 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.4 Hz, 1H), 7.16-7.00 (m,4H), 6.61 (d, J=8.4 Hz, 1H), 5.14-5.00 (m, 1H), 4.27 (s, 1H), 4.04 (dd,J=13.8, 3.6 Hz, 1H), 3.78-3.57 (m, 6H), 3.40 (dd, J=13.7, 8.2 Hz, 1H),2.97-2.79 (m, 6H), 2.66-2.53 (m, 4H), 2.48 (s, 2H), 2.12-2.02 (m, 2H),1.89-1.76 (m, 2H), 1.48 (s, 3H), 1.43 (s, 3H).

Example 235: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[(3R)-1-methyl-3-piperidyl]oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one

The title compound was synthesized in the same manner as in Examples144-1 and 114-3 to 144-6, except that1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol was used insteadof 1-[(4-methoxyphenyl)methylamino]propan-2-ol in Example 144-1, andtert-butyl 3-hydroxypiperidine-1-carboxylate was used instead oftert-butyl 4-hydroxypiperidine-1-carboxylate in Example 144-3.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.4 Hz, 1H), 7.17-7.02 (m,4H), 6.63 (d, J=8.4 Hz, 1H), 5.18 (s, 1H), 4.27 (s, 1H), 4.04 (dd,J=13.8, 3.6 Hz, 1H), 3.76 (s, 2H), 3.71-3.56 (m, 2H), 3.39 (dd, J=13.8,8.3 Hz, 1H), 2.99-2.81 (m, 5H), 2.64 (dd, J=6.3, 2.8 Hz, 2H), 2.60 (d,J=6.8 Hz, 1H), 2.52-2.35 (m, 2H), 2.33 (s, 3H), 2.02-1.84 (m, 2H),1.75-1.58 (m, 2H), 1.47 (s, 3H), 1.42 (s, 3H).

Example 236: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)-3-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 236-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one;dihydrochloride

The title compound was synthesized in the same manner as in Examples 77and 78-1, except that tert-butyl(R)-3-methylsulfonyloxypiperidine-1-carboxylate was used instead oftert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate in Example 77.

Example 236-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)-3-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one;dihydrochloride obtained in Example 236-1 as a starting material wasused in the same manner as in Example 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.19-6.98 (m,4H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.60 (d, J=2.5 Hz, 1H), 4.66 (td,J=5.0, 2.2 Hz, 1H), 4.57-4.41 (m, 4H), 4.23 (tdd, J=7.5, 5.4, 3.7 Hz,1H), 3.97 (dd, J=13.9, 3.7 Hz, 1H), 3.80-3.68 (m, 4H), 3.43 (dd, J=13.9,7.6 Hz, 1H), 3.06 (d, J=11.4 Hz, 1H), 2.98-2.85 (m, 4H), 2.85-2.71 (m,3H), 2.70-2.61 (m, 2H), 2.36 (ddd, J=21.3, 11.4, 5.6 Hz, 2H), 2.04 (d,J=8.9 Hz, 1H), 1.86 (dt, J=8.4, 4.3 Hz, 1H), 1.76-1.62 (m, 1H),1.59-1.48 (m, 1H).

Example 237: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one;dihydrochloride obtained in Example 236-1 as a starting material wasused in the same manner as in Example 162 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.19-6.99 (m,4H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 4.50 (dt,J=22.5, 4.6 Hz, 3H), 4.24 (tt, J=7.8, 4.1 Hz, 1H), 3.97 (dd, J=13.9, 3.7Hz, 1H), 3.81 (s, 2H), 3.72 (q, J=5.9 Hz, 4H), 3.44 (dd, J=13.9, 7.5 Hz,1H), 3.14-3.04 (m, 1H), 2.94 (dt, J=9.5, 4.8 Hz, 4H), 2.82 (dd, J=10.8,5.0 Hz, 1H), 2.67 (dt, J=17.1, 5.2 Hz, 3H), 2.49-2.32 (m, 2H), 2.05 (d,J=10.2 Hz, 2H), 1.87 (s, 1H), 1.70 (dt, J=9.5, 4.1 Hz, 1H), 1.64-1.51(m, 1H).

Example 238: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 as a starting material was usedin the same manner as in Example 220 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.7 Hz, 1H), 7.17-6.99 (m,4H), 6.76 (dd, J=8.8, 2.4 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.46 (q,J=11.0, 8.0 Hz, 3H), 4.24 (s, 1H), 3.97 (dd, J=13.9, 3.7 Hz, 1H),3.83-3.68 (m, 4H), 3.44 (dd, J=13.9, 7.6 Hz, 1H), 2.93 (dd, J=13.7, 4.6Hz, 6H), 2.75-2.53 (m, 4H), 2.42 (d, J=7.6 Hz, 2H), 2.03 (s, 2H), 1.83(d, J=9.5 Hz, 2H), 1.22 (s, 6H).

Example 239: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-fluoro-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 6-fluoro-2-pyridylboronic acid was used instead ofisobutylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 8.03 (q, J=8.1 Hz, 1H), 7.92-7.78 (m,3H), 7.75 (d, J=1.7 Hz, 1H), 7.17-7.01 (m, 5H), 4.55 (t, J=5.1 Hz, 2H),4.33-4.21 (m, 1H), 4.02 (dd, J=13.8, 3.6 Hz, 1H), 3.85-3.70 (m, 4H),3.49 (dd, J=13.8, 7.7 Hz, 1H), 3.01-2.86 (m, 4H), 2.75-2.64 (m, 2H).

Example 240: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-ethoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 163 to obtain the title compound, except that1-bromo-2-ethoxyethane was used instead of 2-fluoroethylpara-toluenesulfonate.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.7 Hz, 1H), 7.16-6.99 (m,4H), 6.79 (dd, J=8.7, 2.5 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.79 (td,J=6.9, 3.3 Hz, 1H), 4.53 (dp, J=7.7, 3.7 Hz, 1H), 4.29-4.19 (m, 1H),4.14 (dd, J=13.9, 3.7 Hz, 1H), 3.79 (s, 2H), 3.68-3.58 (m, 3H),3.58-3.43 (m, 3H), 3.24 (dd, J=13.8, 8.1 Hz, 1H), 2.93 (qd, J=9.2, 8.7,4.5 Hz, 6H), 2.76 (t, J=5.6 Hz, 2H), 2.64 (dt, J=16.5, 7.0 Hz, 4H), 2.07(ddd, J=16.6, 10.3, 6.3 Hz, 2H), 1.93-1.81 (m, 2H), 1.32 (d, J=6.4 Hz,3H), 1.22 (t, J=7.0 Hz, 3H).

Example 241: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-hydroxy]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

Example 241-1: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in the same manner as in Example 140 except that[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate wasused instead of[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as astarting material and the method in the same manner as in Example 64except that tert-butyl3-methylsulfonyloxy-8-azabicyclo[3.2.1]octane-8-carboxylate is usedinstead of 4-chlorotetrahydropyran. The obtained intermediate wasdissolved in methanol, and 4 N hydrochloric acid solution dissolved in1,4-dioxane was added thereto. The reaction solution was stirred at roomtemperature until the reaction was terminated, diluted with ethyldiethylether and filtered to obtain the title compound as a white solid in theform of dihydrochloride.

Example 241-2: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-hydroxy]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 241-1 as a starting material wasused in the same manner as in Example 162 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.8 Hz, 1H), 7.19-6.99 (m,4H), 6.79 (dd, J=8.7, 2.5 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.81-4.74 (m,2H), 4.24 (d, J=5.4 Hz, 1H), 4.15 (dd, J=13.8, 3.6 Hz, 1H), 3.79-3.58(m, 7H), 3.55-3.45 (m, 1H), 3.23 (d, J=5.5 Hz, 1H), 3.00-2.77 (m, 6H),2.66 (h, J=5.2 Hz, 2H), 2.15 (s, 4H), 1.97-1.80 (m, 4H), 1.33 (d, J=6.4Hz, 3H).

Example 242: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 241-1 as a starting material wasused in the same manner as in Example 163 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.61 (d, J=8.7 Hz, 1H), 7.17-7.00 (m,4H), 6.77 (dd, J=8.7, 2.5 Hz, 1H), 6.52 (d, J=2.4 Hz, 1H), 4.78 (td,J=6.9, 3.3 Hz, 1H), 4.73-4.62 (m, 1H), 4.54 (t, J=5.0 Hz, 1H), 4.16(ddd, J=23.5, 11.6, 8.0 Hz, 2H), 3.77 (d, J=9.9 Hz, 3H), 3.63 (dd,J=15.6, 3.4 Hz, 1H), 3.53-3.41 (m, 2H), 3.23 (dd, J=13.8, 8.2 Hz, 1H),2.96-2.91 (m, 4H), 2.88 (td, J=6.4, 5.7, 2.7 Hz, 3H), 2.81 (t, J=5.0 Hz,1H), 2.70 (dd, J=12.9, 4.1 Hz, 1H), 2.62 (dt, J=13.0, 6.5 Hz, 2H),2.12-2.00 (m, 3H), 1.89-1.77 (m, 3H), 1.33 (d, J=6.4 Hz, 3H).

Example 243: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-pyridyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 as a starting material was usedin the same manner as in Example 224 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.20-7.01 (m,4H), 6.77 (dd, J=8.8, 2.5 Hz, 1H), 6.59 (d, J=2.4 Hz, 1H), 4.50 (dt,J=25.8, 4.4 Hz, 3H), 4.30-4.19 (m, 1H), 3.97 (dd, J=13.9, 3.7 Hz, 1H),3.84-3.67 (m, 4H), 3.60 (t, J=5.5 Hz, 2H), 3.45 (dd, J=13.9, 7.6 Hz,1H), 3.38 (s, 3H), 2.93 (dt, J=11.0, 5.7 Hz, 6H), 2.76 (t, J=5.5 Hz,2H), 2.72-2.54 (m, 4H), 2.06 (dd, J=18.1, 11.0 Hz, 2H), 1.93-1.82 (m,2H).

Example 244: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-methoxy-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 12,except that 6-methoxy-2-pyridylboronic acid was used instead ofisobutylboronic acid.

¹H NMR (400 MHz, Methanol-d₄) δ 7.90 (dd, J=8.3, 1.7 Hz, 1H), 7.84-7.69(m, 3H), 7.52 (d, J=7.4 Hz, 1H), 7.18-7.01 (m, 4H), 6.78 (d, J=8.2 Hz,1H), 4.54 (t, J=5.1 Hz, 2H), 4.33-4.21 (m, 1H), 4.03 (s, 4H), 3.82-3.71(m, 4H), 3.49 (dd, J=13.9, 7.7 Hz, 1H), 3.00-2.82 (m, 4H), 2.74-2.62 (m,2H).

Example 245: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 212 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.7 Hz, 1H), 7.17-7.00 (m,4H), 6.79 (dd, J=8.7, 2.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 4.82-4.77 (m,1H), 4.56 (s, 1H), 4.24 (tt, J=8.3, 4.6 Hz, 1H), 4.13 (ddd, J=13.9, 7.8,5.4 Hz, 1H), 4.00 (p, J=6.3 Hz, 1H), 3.79 (s, 2H), 3.64 (dd, J=15.6, 3.4Hz, 1H), 3.50 (dd, J=15.6, 7.6 Hz, 1H), 3.27-3.21 (m, 1H), 3.10-2.87 (m,6H), 2.80-2.62 (m, 4H), 2.57 (d, J=6.4 Hz, 2H), 2.17-2.04 (m, 2H), 1.94(s, 2H), 1.33 (d, J=6.4 Hz, 3H), 1.19 (d, J=6.2 Hz, 3H).

Example 246: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

Example 246-1: Synthesis of8-acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-Chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one (200 mg, 0.48 mmol), tributyl(1-ethoxyvinyl)tin (0.21 mL, 0.62 mmol) andtetrakis(triphenylphosphine)palladium (28 mg, 0.024 mmol) were dissolvedin 4 mL of toluene 4 mL, and the reaction was carried out by the use ofa microwave at 120° C. for 2 hours. To the reaction solutionconcentrated hydrochloric acid aqueous solution and 1,4-dioxane wereadded, followed by stirring at room temperature for 10 minutes. Thereaction solution was diluted with ethyl acetate and basified withsodium hydroxide aqueous solution. The mixture was extracted with ethylacetate, dried over magnesium sulfate and purified by flashchromatography to obtain the title compound.

Example 246-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-Acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one obtained in Example 246-1 as astarting material was used in the same manner as in Example 221-2 toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.13 (d, J=7.8 Hz, 1H), 7.39 (dd, J=7.8,1.2 Hz, 1H), 7.17-7.00 (m, 4H), 4.29 (s, 1H), 4.05 (ddd, J=13.7, 7.3,3.8 Hz, 1H), 3.77 (s, 2H), 3.70 (t, J=4.7 Hz, 4H), 3.62 (d, J=2.4 Hz,2H), 3.55-3.39 (m, 2H), 2.99-2.80 (m, 4H), 2.72-2.61 (m, 2H), 2.64-2.52(m, 2H), 2.41 (dt, J=11.0, 4.6 Hz, 2H), 1.50 (d, J=2.3 Hz, 3H), 1.44 (d,J=2.2 Hz, 3H), 1.39 (d, J=6.8 Hz, 3H).

Example 247: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-Acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one obtained in Example 246-1 as astarting material was used in the same manner as in Example 222 toobtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.13 (d, J=7.8 Hz, 1H), 7.28 (d, J=7.8Hz, 1H), 7.15-7.03 (m, 4H), 4.75 (s, 4H), 4.28 (s, 1H), 4.05 (ddd,J=12.9, 8.5, 3.8 Hz, 1H), 3.76 (s, 2H), 3.61 (d, J=2.1 Hz, 2H),3.49-3.37 (m, 6H), 2.97-2.82 (m, 4H), 2.65 (dd, J=6.3, 3.8 Hz, 2H), 1.50(d, J=2.8 Hz, 3H), 1.44 (d, J=2.8 Hz, 3H), 1.25 (d, J=6.6 Hz, 3H).

Example 248: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-pyrido[3,2-f][1,4]oxazepin-5-onedihydrochloride as a starting material was used in the same manner as inExample 212 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.4 Hz, 1H), 7.15-7.02 (m,4H), 6.60 (d, J=8.4 Hz, 1H), 5.07 (s, 1H), 4.26 (s, 1H), 4.03 (dd,J=13.6, 3.6 Hz, 1H), 3.96 (q, J=6.0 Hz, 1H), 3.75 (s, 2H), 3.71-3.57 (m,2H), 3.41 (dd, J=13.8, 8.2 Hz, 1H), 2.90 (dd, J=19.1, 5.4 Hz, 6H), 2.63(dd, J=6.2, 3.0 Hz, 2H), 2.53 (s, 1H), 2.41 (d, J=8.6 Hz, 3H), 2.06 (s,2H), 1.85 (s, 2H), 1.48 (s, 3H), 1.43 (s, 3H), 1.17 (d, J=6.2 Hz, 3H).

Example 249: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (d, J=8.0 Hz, 1H), 7.22 (dd, J=8.0,1.6 Hz, 1H), 7.17-6.99 (m, 5H), 6.59-6.50 (m, 1H), 6.11-5.97 (m, 1H),5.74 (dd, J=3.5, 1.6 Hz, 1H), 4.48 (t, J=5.1 Hz, 2H), 4.24 (tdd, J=7.3,5.2, 3.5 Hz, 1H), 3.99 (ddd, J=9.5, 4.3, 2.6 Hz, 3H), 3.77 (d, J=2.3 Hz,2H), 3.72 (d, J=7.3 Hz, 4H), 3.62 (s, 2H), 3.46 (dd, J=13.9, 7.6 Hz,1H), 2.96-2.91 (m, 2H), 2.91-2.83 (m, 4H), 2.67 (dd, J=6.2, 2.2 Hz, 2H).

Example 250: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 28,except that(2R)-8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onewas used as a starting material.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=7.9 Hz, 1H), 7.17-7.01 (m,5H), 6.95 (d, J=1.6 Hz, 1H), 4.84-4.78 (m, 1H), 4.75 (s, 3H), 4.23 (td,J=7.9, 4.2 Hz, 1H), 4.15 (dd, J=13.8, 3.7 Hz, 1H), 3.77 (s, 2H),3.66-3.56 (m, 3H), 3.46 (s, 5H), 3.26 (dd, J=13.8, 8.1 Hz, 1H),2.97-2.83 (m, 4H), 2.64 (h, J=7.6 Hz, 2H), 1.31 (d, J=6.3 Hz, 4H).

Example 251: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 29,except that 2-oxa-7-azaspiro[3.5]nonane oxalate was used instead of3-methoxyazetidine hydrochloride.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.0 Hz, 1H), 7.19-6.97 (m,6H), 4.47 (t, J=5.1 Hz, 2H), 4.42 (s, 4H), 4.28-4.19 (m, 1H), 3.99 (dd,J=13.9, 3.6 Hz, 1H), 3.78-3.67 (m, 4H), 3.51-3.40 (m, 3H), 2.93 (dd,J=9.0, 4.0 Hz, 2H), 2.86 (dd, J=8.9, 3.7 Hz, 2H), 2.67-2.60 (m, 2H),2.37 (s, 4H), 1.89 (t, J=5.5 Hz, 4H).

Example 252: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 251,except that(2R)-8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onewas used as a starting material.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=7.9 Hz, 1H), 7.20-6.95 (m,6H), 4.83-4.77 (m, 1H), 4.42 (s, 4H), 4.27-4.20 (m, 1H), 4.16 (dd,J=13.8, 3.7 Hz, 1H), 3.75 (d, J=5.4 Hz, 2H), 3.62 (dd, J=15.6, 3.6 Hz,1H), 3.52-3.41 (m, 3H), 3.26 (dd, J=13.7, 8.1 Hz, 1H), 2.96-2.82 (m,4H), 2.63 (h, J=7.5 Hz, 2H), 2.38 (s, 4H), 1.90 (t, J=5.6 Hz, 4H), 1.31(d, J=6.4 Hz, 3H).

Example 253: Synthesis of4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

Example 253-1: Synthesis of4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)]-8-[[(3R,4R)-3-fluoro-1-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate in which Boc is substituted was synthesized in the samemanner as in Example 140 except that (S)-tert-butyl3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate was used insteadof 4-chlorotetrahydropyran. The obtained intermediate was dissolved inmethanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxanewas added thereto. The reaction solution was stirred at room temperatureuntil the reaction was terminated, diluted with ethyldiethyl ether andfiltered to obtain the title compound as a white solid in the form ofdihydrochloride.

Example 253-2: Synthesis of4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The material obtained in Example 253-1 as a starting material was usedin the same manner as in Example 162, and then the title compound wasobtained by forming hydrochloride salt.

¹H NMR (400 MHz, Methanol-d₄) δ 7.76 (d, J=8.7 Hz, 1H), 7.40-7.19 (m,4H), 6.94 (d, J=8.7 Hz, 1H), 6.80 (s, 1H), 5.13 (d, J=43.3 Hz, 1H), 4.97(s, 1H), 4.67 (dd, J=15.4, 8.5 Hz, 1H), 4.57 (ddd, J=10.7, 7.0, 3.6 Hz,1H), 4.53-4.42 (m, 3H), 4.05-3.83 (m, 5H), 3.77 (ddd, J=9.9, 8.1, 5.1Hz, 5H), 3.65-3.57 (m, 2H), 3.54-3.36 (m, 6H), 3.29-3.07 (m, 2H),2.53-2.18 (m, 2H).

Example 254: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedivalnet hydrochloride

The material obtained in Example 253-1 as a starting material was usedin the same manner as in Example 212, and then the title compound wasobtained by forming hydrochloride salt.

¹H NMR (400 MHz, Methanol-d₄) δ 7.76 (d, J=8.6 Hz, 1H), 7.32 (q, J=7.5,6.7 Hz, 3H), 7.23 (t, J=7.0 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.79 (s,1H), 5.23-5.01 (m, 1H), 4.96 (s, 1H), 4.67 (dd, J=15.4, 8.3 Hz, 1H),4.56 (ddd, J=10.8, 7.0, 3.5 Hz, 1H), 4.52-4.41 (m, 3H), 4.26 (s, 1H),3.98-3.70 (m, 7H), 3.63-3.35 (m, 7H), 3.29-3.06 (m, 4H), 2.60-2.18 (m,2H), 1.29-1.25 (m, 3H).

Example 255: Synthesis of(2R)-4-[(2R)-3-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

Example 255-1: Synthesis of(2R)-4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)]-8-[[(3R,4R)-3-fluoro-1-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate in which Boc is substituted was synthesized by usingthe material obtained in the same manner as in Examples 140-1 to 140-5except that[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate wasused instead of[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate as astarting material and the method in the same manner as in Example 64except that (S)-tert-butyl3-fluoro-4-methylsulfonyloxy-piperidine-1-carboxylate is used instead of4-chlorotetrahydropyran. The obtained intermediate was dissolved inmethanol, and 4 N hydrochloric acid solution dissolved in 1,4-dioxanewas added thereto. The reaction solution was stirred at room temperatureuntil the reaction was terminated, diluted with ethyldiethyl ether andfiltered to obtain the title compound as a white solid in the form ofdihydrochloride.

Example 255-2: Synthesis of(2R)-4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

(2R)-4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)]-8-[[(3R,4R)-3-fluoro-1-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 255-1 as a starting material wasused in the same manner as in Example 162, and then the title compoundwas obtained by forming hydrochloride salt.

¹H NMR (400 MHz, Methanol-d₄) δ 7.70 (dd, J=8.8, 3.7 Hz, 1H), 7.39-7.20(m, 4H), 6.96 (d, J=8.9 Hz, 1H), 6.77 (s, 1H), 5.13 (d, J=43.3 Hz, 1H),4.97 (s, 1H), 4.79 (s, 1H), 4.68 (dd, J=15.3, 7.4 Hz, 1H), 4.55-4.42 (m,2H), 3.96 (dt, J=14.4, 4.3 Hz, 5H), 3.71 (d, J=14.7 Hz, 3H), 3.64-3.35(m, 10H), 3.30-3.13 (m, 2H), 2.57-2.20 (m, 2H), 1.36 (d, J=6.3 Hz, 3H).

Example 256: Synthesis of8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

Example 256-1: Synthesis of8-[(3,3-difluoro-4-piperidyl)oxy]-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5-one

The material, which is obtained by changing1-[(4-methoxyphenyl)methylamino]propan-2-ol to 1-[(4-methoxyphenyl)methylamino]-2-methyl-propan-2-ol in Example 144, as a starting materialwas used in the same manner as in Examples 144-1 to 144-4 to obtain thetitle compound, except that tert-butyl3,3-difluoro-4-hydroxypiperidine-1-carboxylate was used instead oftert-butyl 4-hydroxypiperidine-1-carboxylate in Example 144-3.

Example 256-2: Synthesis of8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5-one

8-[(3,3-Difluoro-4-piperidyl)oxy]-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5-oneobtained in Example 256-1 as a starting material was used in the samemanner as in Example 163 to obtain the title compound, except that2-iodoethanol was used instead of 2-fluoroethyl para-toluenesulfonate.

Example 256-3: Synthesis of8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

8-[[3,3-Difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3,4-dihydropyrido[3,2-f][1,4]oxazepin-5-oneobtained in Example 256-2 as a starting material was used in the samemanner as in Example 5 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.10 (d, J=8.4 Hz, 1H), 7.18-7.02 (m,4H), 6.70 (d, J=8.4 Hz, 1H), 5.49-5.36 (m, 1H), 4.27 (s, 1H), 4.11-3.97(m, 1H), 3.77 (s, 2H), 3.71 (t, J=5.8 Hz, 2H), 3.69-3.58 (m, 2H), 3.44(dd, J=14.4, 8.9 Hz, 1H), 3.08 (s, 1H), 2.91 (dd, J=16.5, 5.2 Hz, 4H),2.81 (s, 2H), 2.73-2.54 (m, 5H), 2.23-2.09 (m, 1H, 1.94 (s, 1H), 1.48(d, J=1.5 Hz, 3H), 1.44 (d, J=1.7 Hz, 3H).

Example 257: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

Example 257-1: Synthesis of8-acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-Bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(200 mg, 0.464 mmol) obtained in Example 10-1,tributyl(1-ethoxyvinyl)tin (204 μl. 0.603 mmol),tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.023 mmol) were addedto 4 mL of toluene and heated to reflux for one day, while stirring.After completion of the reaction, 35% hydrochloric acid aqueous solutionwas added and stirred for 1 hour, followed by basification with sodiumhydroxide aqueous solution until the pH reached 14, followed byextraction with ethyl acetate. The organic layer was dried overanhydrous magnesium sulfate, filtered, concentrated under reducedpressure and purified by flash chromatography to obtain the titlecompound (80 mg).

Example 257-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-Acetyl-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,3-dihydro-1,4-benzoxazepin-5-one(100 mg, 0.254 mmol) obtained in Example 257-1, piperidine (50 μl, 0.508mmol) and titanium(IV) isopropoxide (223 μl, 0.762 mmol) were dissolvedin tetrahydrofuran and heated to reflux for 4 hours. Then, sodiumcyanoborohydride (64 mg, 1.016 mmol) was added thereto and heated to 45°C. and stirred for one day. After completion of the reaction, thereaction solution was extracted with saturated aqueous sodium chloridesolution and ethyl acetate and purified by flash chromatography toobtain the title compound (6 mg).

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.0 Hz, 1H), 7.21-7.00 (m,6H), 4.49 (t, J=5.1 Hz, 2H), 4.23 (q, J=7.3, 5.7 Hz, 1H), 3.99 (dd,J=13.9, 3.7 Hz, 1H), 3.81-3.68 (m, 4H), 3.55 (q, J=6.8 Hz, 1H), 3.47(dd, J=13.9, 7.6 Hz, 1H), 2.99-2.85 (m, 4H), 2.71-2.62 (m, 2H), 2.56 (s,2H), 2.51-2.41 (m, 2H), 2.04 (d, J=9.5 Hz, 1H), 1.62 (q, J=5.9, 5.3 Hz,4H), 1.43 (d, J=6.8 Hz, 4H).

Example 258: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-hydroxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 257,except that 4-hydroxypiperidine was used instead of piperidine inExample 257-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.0 Hz, 1H), 7.22-7.00 (m,6H), 4.49 (t, J=5.1 Hz, 2H), 4.25 (dt, J=7.7, 3.7 Hz, 1H), 3.98 (dd,J=13.9, 3.7 Hz, 1H), 3.81 (s, 2H), 3.73 (t, J=5.1 Hz, 2H), 3.64-3.53 (m,2H), 3.48 (dd, J=13.9, 7.5 Hz, 1H), 2.94 (dp, J=8.9, 4.6, 3.7 Hz, 5H),2.83-2.73 (m, 1H), 2.73-2.61 (m, 2H), 2.24 (t, J=10.7 Hz, 2H), 1.93-1.79(m, 2H), 1.70-1.50 (m, 2H), 1.43 (d, J=6.7 Hz, 3H).

Example 259: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-methoxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 257,except that 4-methoxypiperidine was used instead of piperidine inExample 257-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (d, J=8.0 Hz, 1H), 7.20-7.00 (m,6H), 4.49 (t, J=5.1 Hz, 2H), 4.30-4.19 (m, 1H), 3.98 (dd, J=13.9, 3.7Hz, 1H), 3.79 (d, J=2.2 Hz, 2H), 3.73 (q, J=6.0, 5.1 Hz, 2H), 3.57-3.42(m, 2H), 3.24 (tt, J=8.2, 3.9 Hz, 1H), 2.93 (dt, J=8.0, 4.2 Hz, 5H),2.76-2.64 (m, 3H), 2.31-2.18 (m, 2H), 1.93 (d, J=11.5 Hz, 2H), 1.62-1.52(m, 2H), 1.41 (d, J=6.8 Hz, 3H).

Example 260: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(3-hydroxy-3-methyl-pyrrolidin-1-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 257,except that 3-methylpyrrolidin-3-ol was used instead of piperidine inExample 257-2.

¹H NMR (400 MHz, Methanol-d₄) δ 7.69 (dd, J=8.0, 1.4 Hz, 1H), 7.21 (dd,J=8.1, 1.8 Hz, 1H), 7.16-6.96 (m, 5H), 4.49 (t, J=5.1 Hz, 2H), 4.25 (qd,J=7.6, 4.6 Hz, 1H), 3.98 (dd, J=13.9, 3.7 Hz, 1H), 3.80 (d, J=2.2 Hz,2H), 3.73 (q, J=6.5, 5.1 Hz, 2H), 3.52-3.42 (m, 2H), 2.93 (dt, J=10.1,5.1 Hz, 4H), 2.82-2.49 (m, 6H), 1.89 (td, J=7.4, 3.2 Hz, 2H), 1.42 (t,J=6.2 Hz, 3H), 1.35 (s, 3H).

Example 261: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedi hydrochloride

The title compound was obtained by forming hydrochlodie salt with(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 219.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (dt, J=9.1, 4.6 Hz, 1H), 7.40-7.18(m, 4H), 6.95-6.80 (m, 1H), 6.68 (d, J=15.4 Hz, 1H), 4.81-4.62 (m, 4H),4.47 (dd, J=15.3, 10.2 Hz, 2H), 4.12 (dd, J=10.9, 5.7 Hz, 1H), 4.04-3.80(m, 5H), 3.78-3.36 (m, 9H), 3.31-3.01 (m, 4H), 2.40 (d, J=14.1 Hz, 1H),2.23 (d, J=12.5 Hz, 2H), 2.07-1.94 (m, 1H), 1.36 (d, J=6.3 Hz, 3H).

Example 262: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-piperidyloxy)-3H-pyrido[3,2-f][1,4]oxazepin-5-onedihydrochloride as a starting material was used in the same manner as inExample 224 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 8.04 (d, J=8.4 Hz, 1H), 7.16-7.01 (m,4H), 6.60 (d, J=8.4 Hz, 1H), 5.07 (dt, J=8.3, 4.2 Hz, 1H), 4.32-4.20 (m,1H), 4.03 (dd, J=13.8, 3.6 Hz, 1H), 3.75 (s, 2H), 3.71-3.60 (m, 2H),3.57 (t, J=5.6 Hz, 2H), 3.41 (dd, J=13.8, 8.2 Hz, 3H), 3.36 (s, 4H),2.93 (d, J=5.7 Hz, 2H), 2.91-2.78 (m, 4H), 2.64 (q, J=5.2, 4.4 Hz, 4H),2.47 (t, J=9.9 Hz, 2H), 2.12-2.01 (m, 2H), 1.83 (q, J=16.6, 13.0 Hz,2H), 1.48 (s, 3H), 1.43 (s, 3H).

Example 263: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

Example 263-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The material, which is obtained by changing 4-chlorotetrahydropyran to(S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol in Example 64, as a startingmaterial was used in the same manner as in Example 78-1 to obtain thetitle compound.

Example 263-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 263-1 as a starting material wasused in the same manner as in Example 87 to obtain the title compound,except that oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.19-7.00 (m,4H), 6.73 (dd, J=8.8, 2.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 5.02-4.94 (m,1H), 4.75 (t, J=6.7 Hz, 2H), 4.64 (dt, J=11.8, 6.1 Hz, 2H), 4.48 (t,J=5.0 Hz, 2H), 4.23 (q, J=7.2, 5.8 Hz, 1H), 3.97 (dd, J=13.9, 3.7 Hz,1H), 3.82-3.65 (m, 5H), 3.43 (dd, J=13.9, 7.6 Hz, 1H), 3.00-2.87 (m,5H), 2.87-2.79 (m, 2H), 2.70-2.62 (m, 2H), 2.56 (td, J=8.5, 6.2 Hz, 1H),2.38 (dq, J=14.0, 7.1 Hz, 1H), 2.06-1.95 (m, 1H).

Example 264: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

Example 264-1: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Examples140-1 to 140-5, except that[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate wasused instead of[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate in Example140-1.

Example 264-2: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate was synthesized by using(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 264-1 as a starting material in the same manner asin Example 64 except that (S)-1-(tert-butoxycarbonyl)-3-pyrrolidinol isused instead of 4-chlorotetrahydropyran. 4 M hydrochloric acid solutiondissolved in 1,4-dioxane was slowly added thereto. The reaction solutionwas stirred at room temperature, diluted with diethyl ether and filteredto obtain the title compound as a white solid.

Example 264-3: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 264-2 as a starting material wasused in the same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.56 (d, J=8.7 Hz, 1H), 7.11-6.92 (m,4H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 4.93 (s, 1H),4.72 (td, J=7.2, 3.4 Hz, 1H), 4.23-4.11 (m, 1H), 4.07 (dd, J=13.9, 3.7Hz, 1H), 3.73 (s, 2H), 3.56 (dd, J=15.6, 3.4 Hz, 1H), 3.42 (dd, J=15.6,7.6 Hz, 1H), 3.17 (dd, J=13.8, 8.1 Hz, 1H), 3.02-2.79 (m, 7H), 2.68-2.49(m, 3H), 2.42 (s, 4H), 1.96 (dt, J=14.8, 6.6 Hz, 1H), 1.26 (d, J=6.4 Hz,3H).

Example 265: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3R)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that [(3S)-tetrahydrofuran-3-yl]methanesulfonate was used insteadof 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.7 Hz, 1H), 7.21-6.98 (m,4H), 6.74 (dd, J=8.8, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.07 (d,J=5.6 Hz, 1H), 4.48 (t, J=5.0 Hz, 2H), 4.24 (s, 1H), 4.04-3.85 (m, 5H),3.85-3.67 (m, 4H), 3.44 (dd, J=13.8, 7.6 Hz, 1H), 3.03-2.84 (m, 4H),2.75-2.60 (m, 2H), 2.33-2.23 (m, 1H), 2.16-2.05 (m, 1H).

Example 266: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3S)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

The title compound was synthesized in the same manner as in Example 64,except that [(3R)-tetrahydrofuran-3-yl]methanesulfonate was used insteadof 4-chlorotetrahydropyran.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.19-6.99 (m,4H), 6.74 (dd, J=8.8, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 5.13-5.02 (m,1H), 4.48 (t, J=5.0 Hz, 2H), 4.23 (q, J=7.5, 5.9 Hz, 1H), 4.02-3.84 (m,5H), 3.82-3.69 (m, 4H), 3.44 (dd, J=13.9, 7.6 Hz, 1H), 3.00-2.82 (m,4H), 2.67 (dd, J=6.2, 2.3 Hz, 2H), 2.36-2.21 (m, 1H), 2.12 (dt, J=12.7,5.8 Hz, 1H).

Example 267: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2S)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 212 to obtain the title compound, except that (S)-2-methoxiranewas used instead of 2-methoxirane.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.16-6.97 (m,4H), 6.78 (dd, J=8.7, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.79 (td,J=7.1, 3.3 Hz, 1H), 4.51 (s, 1H), 4.23 (q, J=8.0, 5.8 Hz, 1H), 4.15 (dd,J=13.7, 3.7 Hz, 1H), 3.97 (dt, J=12.5, 6.2 Hz, 1H), 3.77 (s, 2H), 3.64(dd, J=15.6, 3.4 Hz, 1H), 3.49 (dd, J=15.6, 7.5 Hz, 1H), 3.23 (dd,J=13.7, 8.2 Hz, 1H), 2.99-2.79 (m, 6H), 2.70-2.40 (m, 6H), 2.06 (s, 2H),1.86 (s, 2H), 1.33 (d, J=6.4 Hz, 3H), 1.18 (d, J=6.3 Hz, 3H).

Example 268: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2R)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 212 to obtain the title compound, except that (R)-2-methoxiranewas used instead of 2-methoxirane.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.16-6.99 (m,4H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 4.79 (td,J=7.0, 3.3 Hz, 1H), 4.51 (s, 1H), 4.24 (dt, J=12.8, 6.1 Hz, 1H), 4.15(dd, J=13.8, 3.6 Hz, 1H), 3.97 (h, J=6.2, 5.5 Hz, 1H), 3.77 (s, 2H),3.63 (dd, J=15.6, 3.4 Hz, 1H), 3.49 (dd, J=15.6, 7.6 Hz, 1H), 3.23 (dd,J=13.8, 8.1 Hz, 1H), 2.99-2.80 (m, 6H), 2.69-2.40 (m, 6H), 2.05 (d,J=11.0 Hz, 2H), 1.93-1.80 (m, 2H), 1.33 (d, J=6.4 Hz, 3H), 1.18 (d,J=6.2 Hz, 3H).

Example 269: Synthesis of8-[cyclopropyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one(1 equiv) obtained in Example 216 was dissolved in methanol, and anexcess of sodium borohydride was added thereto. The reaction solutionwas stirred at room temperature for 10 minutes and extracted with ethylacetate. The extracted organic solution was concentrated under reducedpressure and purified by flash chromatography to obtain the titlecompound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.47 (d, J=8.0 Hz, 1H), 7.05 (dd, J=8.1,1.6 Hz, 1H), 6.97-6.82 (m, 5H), 4.28 (t, J=5.2 Hz, 2H), 4.10-4.00 (m,1H), 3.84-3.73 (m, 2H), 3.60 (s, 2H), 3.58-3.44 (m, 3H), 3.26 (dd,J=13.9, 7.6 Hz, 1H), 2.74 (dd, J=10.0, 4.5 Hz, 4H), 2.56-2.42 (m, 2H),0.93 (tdd, J=8.0, 5.4, 3.0 Hz, 1H), 0.48-0.37 (m, 1H), 0.37-0.26 (m,2H), 0.25-0.15 (m, 1H)

Example 270: Synthesis of8-[cyclopentyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one

8-(Cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 217 as a starting material was used in the samemanner as in Example 269 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.66 (d, J=8.0 Hz, 1H), 7.22-7.01 (m,5H), 4.48 (t, J=5.1 Hz, 2H), 4.37 (d, J=8.2 Hz, 1H), 4.25 (s, 1H), 3.99(dd, J=13.9, 3.7 Hz, 1H), 3.79 (s, 2H), 3.71 (t, J=5.3 Hz, 2H), 3.46(dd, J=13.9, 7.7 Hz, 1H), 3.01-2.85 (m, 4H), 2.74-2.61 (m, 2H), 2.19 (q,J=8.2 Hz, 1H), 1.90-1.80 (m, 1H), 1.74-1.46 (m, 6H), 1.44-1.34 (m, 1H),1.30-1.16 (m, 1H).

Example 271: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

Example 271-1: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The material, which is obtained by changing 4-chlorotetrahydropyran to(R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol in Example 64, as a startingmaterial was used in the same manner as in Example 78-1 to obtain thetitle compound.

Example 271-2: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 271-1 as a starting material wasused in the same manner as in Example 87 to obtain the title compoundexcept that oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.8 Hz, 1H), 7.16-7.02 (m,4H), 6.73 (dd, J=8.8, 2.5 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.98 (td,J=6.1, 5.3, 2.8 Hz, 1H), 4.75 (t, J=6.7 Hz, 2H), 4.64 (dt, J=11.8, 6.1Hz, 2H), 4.48 (t, J=4.9 Hz, 2H), 4.23 (qd, J=7.2, 3.7 Hz, 1H), 3.98 (dd,J=13.9, 3.6 Hz, 1H), 3.80-3.71 (m, 5H), 3.42 (dd, J=13.9, 7.7 Hz, 1H),2.98-2.80 (m, 7H), 2.69-2.62 (m, 2H), 2.56 (ddd, J=9.2, 7.8, 6.1 Hz,1H), 2.38 (dq, J=14.0, 7.1 Hz, 1H), 2.01 (dt, J=13.7, 4.4 Hz, 1H).

Example 272: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 271-1 as a starting material wasused in the same manner as in Example 224 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.68 (d, J=8.7 Hz, 1H), 7.18-7.00 (m,4H), 6.71 (dd, J=8.8, 2.5 Hz, 1H), 6.53 (d, J=2.4 Hz, 1H), 4.95 (ddd,J=7.7, 5.7, 2.9 Hz, 1H), 4.48 (t, J=5.0 Hz, 2H), 4.23 (tdd, J=7.6, 6.3,5.2, 3.7 Hz, 1H), 3.98 (dd, J=13.9, 3.6 Hz, 1H), 3.79-3.70 (m, 4H), 3.56(t, J=5.6 Hz, 2H), 3.42 (dd, J=13.9, 7.7 Hz, 1H), 3.36 (s, 3H),2.98-2.86 (m, 6H), 2.75 (tq, J=12.7, 6.4, 5.4 Hz, 2H), 2.66-2.60 (m,2H), 2.37 (dtd, J=13.6, 7.6, 5.9 Hz, 1H), 1.96 (dtd, J=13.2, 6.8, 6.4,2.2 Hz, 1H).

Example 273: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

Example 273-1: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride

The intermediate was synthesized by using(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-hydroxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-oneobtained in Example 264-1 as a starting material in the same manner asin Example 64 except that (R)-1-(tert-butoxycarbonyl)-3-pyrrolidinol wasused instead of 4-chlorotetrahydropyran. 4 M hydrochloric acid solutiondissolved in 1,4-dioxane was slowly added thereto. The reaction solutionwas stirred at room temperature, diluted with diethyl ether and filteredto obtain the title compound as a white solid.

Example 273-2: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 273-1 as a starting material wasused in the same manner as in Example 87 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.55 (d, J=8.7 Hz, 1H), 7.10-6.93 (m,4H), 6.67 (dd, J=8.7, 2.5 Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 4.92 (d,J=6.9 Hz, 1H), 4.72 (td, J=7.0, 3.3 Hz, 1H), 4.16 (dt, J=8.2, 4.1 Hz,1H), 4.06 (dd, J=13.8, 3.6 Hz, 1H), 3.72 (s, 2H), 3.56 (dd, J=15.6, 3.4Hz, 1H), 3.42 (dd, J=15.6, 7.6 Hz, 1H), 3.17 (dd, J=13.8, 8.1 Hz, 1H),2.88 (ddd, J=19.7, 9.7, 6.8 Hz, 7H), 2.65-2.46 (m, 3H), 2.41 (s, 4H),2.00-1.91 (m, 1H), 1.25 (d, J=6.4 Hz, 3H).

Example 274: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 273-1 as a starting material wasused in the same manner as in Example 224 to obtain the title compound.

¹H NMR (400 MHz, Methanol-d₄) δ 7.63 (d, J=8.7 Hz, 1H), 7.17-7.00 (m,4H), 6.73 (dd, J=8.7, 2.5 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 4.95 (ddt,J=7.7, 5.3, 2.5 Hz, 1H), 4.79 (td, J=7.1, 3.3 Hz, 1H), 4.28-4.20 (m,1H), 4.15 (dd, J=13.8, 3.6 Hz, 1H), 3.77 (s, 2H), 3.63 (dd, J=15.6, 3.4Hz, 1H), 3.56 (t, J=5.6 Hz, 2H), 3.49 (dd, J=15.6, 7.5 Hz, 1H), 3.36 (s,3H), 3.23 (dd, J=13.8, 8.2 Hz, 1H), 2.94 (dddd, J=21.2, 15.4, 9.2, 3.8Hz, 7H), 2.84-2.70 (m, 2H), 2.68-2.55 (m, 3H), 2.37 (dtd, J=13.6, 7.6,5.9 Hz, 1H), 1.97 (dq, J=9.9, 7.4 Hz, 1H), 1.33 (d, J=6.4 Hz, 3H).

Example 275: Synthesis of4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 78-1 as a starting material was usedin the same manner as in Example 212 to obtain the title compound,except that 2-(trifluoromethyl)oxirane was used instead of2-methoxirane.

¹H NMR (400 MHz, Methanol-d₄) δ 7.67 (d, J=8.8 Hz, 1H), 7.17-7.02 (m,4H), 6.76 (dd, J=8.8, 2.5 Hz, 1H), 6.58 (d, J=2.4 Hz, 1H), 4.48 (dt,J=9.9, 4.4 Hz, 3H), 4.27-4.14 (m, 2H), 3.97 (dd, J=13.9, 3.6 Hz, 1H),3.78-3.70 (m, 4H), 3.43 (dd, J=13.9, 7.7 Hz, 1H), 2.93 (d, J=5.5 Hz,2H), 2.91-2.81 (m, 4H), 2.70-2.59 (m, 4H), 2.52 (d, J=10.5 Hz, 2H), 2.03(s, 2H), 1.84 (q, J=9.9, 8.8 Hz, 2H).

Example 276: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-2-methyl-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one

The material, which is obtained by changing[2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate to[(1S)-2-(tert-butoxycarbonylamino)-1-methyl-ethyl]methanesulfonate inExample 140, as a starting material was used in the same manner as inExample 212 to obtain the title compound, except that2-(trifluoromethyl)oxirane was used instead of 2-methoxirane.

¹H NMR (400 MHz, Methanol-d₄) δ 7.62 (d, J=8.7 Hz, 1H), 7.20-6.98 (m,4H), 6.78 (dd, J=8.8, 2.5 Hz, 1H), 6.55 (d, J=2.4 Hz, 1H), 4.78 (dd,J=6.8, 3.3 Hz, 1H), 4.53-4.44 (m, 1H), 4.28-4.09 (m, 3H), 3.78 (d,J=11.9 Hz, 2H), 3.63 (dd, J=15.7, 3.4 Hz, 1H), 3.49 (dd, J=15.5, 7.6 Hz,1H), 3.24 (dd, J=13.7, 8.1 Hz, 1H), 3.00-2.80 (m, 6H), 2.64 (dt, J=7.7,4.5 Hz, 4H), 2.52 (q, J=10.3 Hz, 2H), 2.03 (s, 2H), 1.85 (d, J=10.5 Hz,2H), 1.33 (d, J=6.4 Hz, 3H).

Example 277: Synthesis of(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one

(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride obtained in Example 273-1 as a starting material wasused in the same manner as in Example 87 to obtain the title compoundexcept that oxetan-3-one was used instead of paraformaldehyde.

¹H NMR (400 MHz, Methanol-d₄) δ 7.64 (d, J=8.7 Hz, 1H), 7.15-7.01 (m,4H), 6.73 (dd, J=8.7, 2.5 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 4.96 (ddt,J=8.2, 5.4, 2.5 Hz, 1H), 4.76 (dt, J=23.0, 6.8 Hz, 3H), 4.63 (dt,J=11.8, 6.1 Hz, 2H), 4.23 (td, J=7.9, 4.2 Hz, 1H), 4.14 (dd, J=13.8, 3.6Hz, 1H), 3.79-3.69 (m, 3H), 3.62 (dd, J=15.6, 3.4 Hz, 1H), 3.48 (dd,J=15.6, 7.5 Hz, 1H), 3.21 (dd, J=13.8, 8.2 Hz, 1H), 2.98-2.76 (m, 7H),2.66-2.59 (m, 2H), 2.54 (ddd, J=9.3, 7.8, 6.1 Hz, 1H), 2.36 (dq, J=14.0,7.1 Hz, 1H), 2.07-1.94 (m, 1H), 1.32 (d, J=6.4 Hz, 3H).

Experimental Example

Method for Measuring Enzyme Activity

In vitro assay: PRMT5-MEP50 enzyme complex, cofactorS-adenosylmethionine (SAM) and histone H4 peptide were reacted in vitro,and methylation of arginine (H4R3)—which is the third amino acid ofhistone H4—was measured in order to measure the enzyme activity ofPRMT5.

Reagents: PRMT5-MEP50 enzyme complex (Catalog No. 51045), blockingbuffer (52100-B), histone methyltransferase reaction buffer 2 (4×HMTassay buffer 2, Catalog No. 52170), and primary antibody (primaryantibody 4-3, Catalog No. 52150) were purchased from BPS Bioscience(USA). The histone H4 peptide (1-20 amino acids) was custom made byKomabiotech (Korea) and used. S-adenosylmethionine was purchased fromNEB (New England Biolabs, USA, Catalog No. B9003S). Plates for coatinghistone H4 peptide, washing buffer and color development reagent werepurchased from the following vendors: Plate (Immobilizer™-Amino Plate,NUNC, Denmark, Catalog No. 436023), carbonate-bicarbonate buffer(Sigma-Aldrich, USA, Catalog No. C3041), washing buffer (10×TBST,Biosesang, Korea, Catalog No. T2005), TMB ELISA substrate (Abcam, UK,Catalog No. ab210902), horseradish peroxidase (HRP)-conjugated antibody(Abcam, UK, Catalog No. ab6721).

Experimental procedure: The histone H4 peptide was diluted withcarbonate-bicarbonate buffer and prepared to 100 μg/mL, and thendispensed onto the plate per 100 μL and reacted at 37° C. for 1 hour.PRMT5-MEP50 enzyme complex and S-adenosylmethionine were diluted withhistone methyltransferase reaction buffer to prepare 5 μg/mL and 2 μM,respectively, and then 20 μL of PRMT5-MEP50 enzyme complex and 25 μL ofS-adenosylmethionine were dispensed onto the plate prepared above. 5 μLof the compound diluted with 10% dimethyl sulfoxide solution was addedthereto and reacted at room temperature for 2 hours (final volume=50μL). The concentration of the compound was diluted 1:5 from 10 μM untilthe lowest concentration of 0.128 nM, and 8 points were used for thetest. After preparing the primary antibody by diluting 1:2000 withblocking buffer, 100 μL was added to the plate and reacted at roomtemperature for 1 hour. After preparing horseradishperoxidase-conjugated antibody by diluting 1:10,000 with blockingbuffer, 100 μL was added to the plate and reacted at room temperaturefor 1 hour. 100 μL of TMB substrate was added and reacted for 3 minutesat room temperature, and 100 μL of 1 N sulfuric acid was then added toterminate the reaction. Then, the absorbance at 450 nm was measured tocalculate the IC₅₀ value of the compound. (+++: 1 to 100 nM, ++: greaterthan 100 to 1,000 nM, +: greater than 1,000 to 10,000 nM)

TABLE 2 Compound PRMT5 enzyme IC₅₀ (nM) Example 1 ++ Example 2 ++Example 4 ++ Example 5 ++ Example 6 +++ Example 7 ++ Example 8 ++Example 9 ++ Example 10 ++ Example 11 ++ Example 12 +++ Example 13 +++Example 14 ++ Example 15 +++ Example 16 +++ Example 17 +++ Example 18 ++Example 19 ++ Example 20 ++ Example 21 ++ Example 22 +++ Example 23 +++Example 24 +++ Example 25 ++ Example 26 ++ Example 27 +++ Example 28 +++Example 29 ++ Example 30 +++ Example 31 +++ Example 32 +++ Example 33 ++Example 34 +++ Example 35 ++ Example 36 ++ Example 37 + Example 38 ++Example 39 ++ Example 40 +++ Example 41 ++ Example 42 ++ Example 43 +++Example 44 +++ Example 45 +++ Example 46 ++ Example 47 ++ Example 48 ++Example 49 ++ Example 50 +++ Example 51 ++ Example 52 ++ Example 53 ++Example 54 +++ Example 55 ++ Example 56 ++ Example 57 +++ Example 58 +++Example 59 ++ Example 60 ++ Example 61 ++ Example 62 +++ Example 63 +++Example 64 +++ Example 65 ++ Example 66 ++ Example 67 ++ Example 68 ++Example 69 +++ Example 70 ++ Example 71 ++ Example 72 ++ Example 73 ++Example 74 ++ Example 75 ++ Example 76 ++ Example 77 +++ Example 78 +++Example 79 ++ Example 80 ++ Example 81 +++ Example 82 ++ Example 83 ++Example 84 ++ Example 85 +++ Example 86 ++ Example 87 +++ Example 88 +++Example 89 +++ Example 90 +++ Example 91 ++ Example 92 ++ Example 93 ++Example 94 ++ Example 95 ++ Example 96 ++ Example 97 ++ Example 98 ++Example 99 ++ Example 101 ++ Example 102 ++ Example 103 ++ Example 104++ Example 105 ++ Example 106 ++ Example 107 +++ Example 108 + Example109 ++ Example 110 ++ Example 111 ++ Example 112 ++ Example 113 ++Example 114 +++ Example 115 +++ Example 116 ++ Example 117 ++ Example118 +++ Example 119 ++ Example 120 +++ Example 121 ++ Example 122 ++Example 123 ++ Example 124 ++ Example 125 ++ Example 126 ++ Example 127+++ Example 128 ++ Example 129 ++ Example 130 ++ Example 131 ++ Example132 ++ Example 133 +++ Example 134 +++ Example 135 ++ Example 136 ++Example 137 +++ Example 138 ++ Example 139 ++ Example 140 ++ Example 141+++ Example 142 +++ Example 143 ++ Example 144 ++ Example 145 ++ Example146 ++ Example 147 ++ Example 148 + Example 149 ++ Example 150 ++Example 151 +++ Example 152 ++ Example 153 ++ Example 154 +++ Example155 +++ Example 156 +++ Example 157 +++ Example 158 ++ Example 159 ++Example 160 +++ Example 161 +++ Example 162 ++ Example 163 ++ Example164 ++ Example 165 +++ Example 166 ++ Example 167 ++ Example 168 +++Example 169 ++ Example 170 ++ Example 171 +++ Example 172 ++ Example 173+++ Example 174 +++ Example 175 ++ Example 176 ++ Example 177 ++ Example178 ++ Example 179 ++ Example 180 +++ Example 181 ++ Example 182 ++Example 183 ++ Example 184 ++ Example 185 ++ Example 186 ++ Example 187++ Example 188 ++ Example 189 ++ Example 190 ++ Example 191 ++ Example192 ++ Example 193 ++ Example 194 ++ Example 195 ++ Example 196 ++Example 197 ++ Example 198 +++ Example 199 +++ Example 201 ++ Example202 +++ Example 203 ++ Example 204 ++ Example 205 ++ Example 206 ++Example 207 ++ Example 208 ++ Example 209 ++ Example 210 ++ Example 211++ Example 212 ++ Example 213 ++ Example 214 ++ Example 215 ++ Example216 +++ Example 217 ++ Example 218 ++ Example 219 +++ Example 220 ++Example 221 ++ Example 222 ++ Example 223 ++ Example 224 ++ Example 225++ Example 226 +++ Example 227 +++ Example 228 +++ Example 229 ++Example 230 +++ Example 231 +++ Example 232 ++ Example 233 ++ Example234 +++ Example 238 ++ Example 240 ++ Example 241 ++ Example 242 +++Example 243 +++ Example 245 ++ Example 246 ++ Example 247 ++ Example 248+++ Example 249 ++ Example 250 ++ Example 251 ++ Example 252 ++ Example253 ++ Example 254 ++ Example 255 ++ Example 256 ++ Example 261 ++Example 262 ++ Example 264 ++ Example 267 ++ Example 268 ++ Example 272++ Example 273 ++ Example 274 ++

Test for in vivo target inhibitory activity

After U87MG tumor cells were implanted subcutaneously in nude mice, aPRMT5 inhibitor was administered orally (25 or 50 mg/kg) 1-2 times dailyfor one week, and then the degree to which SDMA levels in the tumordecreased was measured.

Reagents: Bradford's solution (Catalog No. 500-0006) was purchased fromBio-rad (USA). SDMA antibody (Catalog No. 13222s) was purchased fromCell Signaling Technology (USA). SmD3 antibody (Catalog No. ap12451a)was purchased from Abgent (USA), and secondary antibody (Catalog No.ab6721) and TMB substrate (Catalog No. ab210902) were purchased fromAbcam (UK).

Experimental procedure: The tumor tissues transplanted into the micewere excised, the cells were lysed, and then quantified with Bradford'ssolution. 5-10 μg of protein per sample was diluted withcarbonate-bicarbonate buffer and dispensed into a 96-well plate andreacted at room temperature for 2 hours. After washing with phosphatebuffered saline (PBST) containing 0.05% Tween-20 3 times, 200 μL of PBSTcontaining 5% bovine serum albumin (BSA-PBST) was added and reacted atroom temperature for 2 hours. After washing with PBST 3 times, the SDMAantibody and the SmD3 antibody were diluted in BSA-PBST, and 100 μL ofeach was dispensed onto the plate and reacted at 4° C. overnight. Afterwashing with PBST 3 times the next day, 100 μL of the secondary antibodydiluted in BSA-PBST was added and reacted at room temperature for 1hour. After washing with PBST 3 times, 100 μL of TMB substrate was addedand reacted at room temperature for 10-20 minutes, and 100 μL of 1Nsulfuric acid solution was added to terminate the reaction. Then, theabsorbance at 450 nm was measured to calculate the degree of SDMAinhibition by the compound. (+++: more than 70%, ++: more than 30% and70% or less, +: 30% or less)

TABLE 3 Compound SDMA inhibition (%) Example 11 ++ Example 22 +++Example 87 +++ Example 88 +++ Example 92 +++ Example 112 +++ Example155 + Example 156 ++

What is claimed is:
 1. A compound of Formula 1, or an optical isomer, astereoisomer or an isotopic variant thereof, or a pharmaceuticallyacceptable salt thereof:

wherein X¹ and X² are each independently carbon or nitrogen; Y iscarbon, oxygen or nitrogen; Z is carbon; n is an integer of 0 or 1; m isan integer of 0 to 2;

is a single bond or a double bond; R¹ is -D-R¹⁰; wherein D is a directbond, —O—, —C(═O)—, —C≡C— or —CR¹¹R¹²—; R¹⁹ is hydrogen, halo, hydroxy,cyano, alkyl, hydroxyalkyl, haloalkyl, haloalkylsulfonate, dialkylamino,alkylaminoalkyl, dialkylaminoalkyl, dialkylaminocarbonylalkyl, saturatedor unsaturated carbocyclyl, saturated or unsaturated heterocyclyl,saturated or unsaturated carbocyclyl-alkyl, or saturated or unsaturatedheterocyclyl-alkyl; R¹¹ and R¹² are each independently hydrogen, hydroxyor alkyl; the carbocycle or heterocycle may be substituted with one ormore substituents selected from hydroxy, halo, oxo, formyl (—CHO),nitrile, alkyl, alkoxy, hydroxyalkyl, hydroxyhaloalkyl, alkoxyalkyl,haloalkyl, nitrilealkyl, alkylcarbonyl, alkylthiocarbonyl,alkoxycarbonyl, haloalkylcarbonyl, carbocyclyl, carbocyclylcarbonyl,(alkyl)(haloalkyl)amino, (alkyl)(heterocyclyl)amino, heterocyclyl andheterocyclyl-alkyl; R² is hydrogen or alkyl; R³ is hydrogen or alkyl;R⁴, R⁵, R⁶ and R⁷ are each independently hydrogen or alkyl; R⁸ ishydrogen, halo, alkyl, alkoxy or amino; and R⁹ is hydrogen, halo oralkyl.
 2. The compound, or optical isomer, stereoisomer or isotopicvariant thereof, or pharmaceutically acceptable salt thereof accordingto claim 1, wherein X¹ and X² are each independently CH or N; Y is CH₂,O or NH, when n is 0; Y is CH or N, when n is 1; Z is CH₂ or CH, when mis 0; Z is CH or C, when m is 1; Z is C, when m is 2; and

is a single bond or a double bond.
 3. The compound, or optical isomer,stereoisomer or isotopic variant thereof, or pharmaceutically acceptablesalt thereof according to claim 1, wherein R¹ is -D-R¹⁰; wherein D is adirect bond, —O—, —C(═O)—, —C≡C— or —CR¹¹R¹²—; R¹⁰ is hydrogen, halo,hydroxy, cyano, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇alkyl,halo-C₁-C₇alkylsulfonate, di(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino-C₁-C₇alkyl, di(C₁-C₇ alkyl)amino-C₁-C₇ alkyl, di(C₁-C₇alkyl)aminocarbonyl-C₁-C₇ alkyl, saturated or unsaturated C₃-C₁₀carbocyclyl, saturated or unsaturated, 4- to 10-membered heterocyclyl,saturated or unsaturated C₃-C₁₀ carbocyclyl-C₁-C₇ alkyl, or saturated orunsaturated, 4- to 10-membered heterocyclyl-alkyl; and R¹¹ and R¹² areeach independently hydrogen, hydroxy or C₁-C₇ alkyl.
 4. The compound, oroptical isomer, stereoisomer or isotopic variant thereof, orpharmaceutically acceptable salt thereof according to claim 3, whereinR¹⁰ is halo, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl,saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated,4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to10-membered heterocyclyl-alkyl.
 5. The compound, or optical isomer,stereoisomer or isotopic variant thereof, or pharmaceutically acceptablesalt thereof according to claim 1, wherein the carbocycle or heterocyclemay be substituted with 1 to 5 substituents selected from hydroxy, halo,oxo, formyl, nitrile, C₁-C₇ alkyl, C₁-C₇ alkoxy, hydroxy-C₁-C₇ alkyl,hydroxyhalo-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl,nitrile-C₁-C₇ alkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkylthiocarbonyl, C₁-C₇alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, saturated or unsaturatedC₃-C₁₀ carbocyclyl, saturated or unsaturated C₃-C₁₀ carbocyclylcarbonyl,(C₁-C₇ alkyl)(halo-C₁-C₇ alkyl)amino, (C₁-C₇ alkyl)(saturated orunsaturated, 4- to 10-membered heterocyclyl)amino, saturated orunsaturated, 4- to 10-membered heterocyclyl and saturated orunsaturated, 4- to 10-membered heterocyclyl-C₁-C₇ alkyl.
 6. Thecompound, or optical isomer, stereoisomer or isotopic variant thereof,or pharmaceutically acceptable salt thereof according to claim 5,wherein the carbocycle or heterocycle may be substituted with 1 to 5substituents selected from hydroxy, halo, formyl, C₁-C₇ alkyl,hydroxy-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, saturatedor unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated C₃-C₁₀carbocyclylcarbonyl, (C₁-C₇ alkyl)(halo-C₁-C₇ alkyl)amino, (C₁-C₇alkyl)(saturated or unsaturated, 4- to 10-membered heterocyclyl)aminoand saturated or unsaturated, 4- to 10-membered heterocyclyl-C₁-C₇alkyl.
 7. The compound, or optical isomer, stereoisomer or isotopicvariant thereof, or pharmaceutically acceptable salt thereof accordingto claim 1, wherein the heterocycle may be substituted with 1 or 2substituents selected from hydroxy, halo, formyl, C₁-C₇ alkyl,hydroxy-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl, C₁-C₇alkylcarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, saturatedor unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated C₃-C₁₀carbocyclylcarbonyl and saturated or unsaturated, 4- to 10-memberedheterocyclyl-C₁-C₇ alkyl.
 8. The compound, or optical isomer,stereoisomer or isotopic variant thereof, or pharmaceutically acceptablesalt thereof according to claim 1, wherein the carbocycle may besubstituted with 1 or 2 substituents selected from halo-C₁-C₇ alkyl,(C₁-C₇ alkyl)(halo-C₁-C₇ alkyl)amino and (C₁-C₇ alkyl)(saturated orunsaturated, 4- to 10-membered heterocyclyl)amino.
 9. The compound, oroptical isomer, stereoisomer or isotopic variant thereof, orpharmaceutically acceptable salt thereof according to claim 1, whereinR¹ is -D-R¹⁰; wherein D is a direct bond; R¹⁰ is hydrogen, halo, cyano,C₁-C₇ alkyl, halo-C₁-C₇ alkyl, di(C₁-C₇ alkyl)amino-C₁-C₇ alkyl,saturated or unsaturated, 4- to 10-membered heterocyclyl, saturated orunsaturated C₃-C₁₀ carbocyclyl, or saturated or unsaturated, 4- to10-membered heterocyclyl-alkyl; and the heterocycle may be substitutedwith 1 or 2 substituents selected from hydroxy, halo, formyl, C₁-C₇alkyl, C₁-C₇ alkoxy, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl,nitrile-C₁-C₇ alkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxy-C₁-C₇ alkyl,C₁-C₇ alkoxycarbonyl, halo-C₁-C₇ alkylcarbonyl, and saturated orunsaturated, 4- to 10-membered heterocyclyl.
 10. The compound, oroptical isomer, stereoisomer or isotopic variant thereof, orpharmaceutically acceptable salt thereof according to claim 1, whereinR² is hydrogen or C₁-C₇alkyl; R³ is hydrogen or C₁-C₇alkyl; R⁴, R⁵, R⁶and R⁷ are each independently hydrogen or C₁-C₇ alkyl; R⁸ is hydrogen,halo, C₁-C₇alkyl, C₁-C₇alkoxy or amino; and R⁹ is hydrogen, halo orC₁-C₇ alkyl.
 11. The compound, or optical isomer, stereoisomer orisotopic variant thereof, or pharmaceutically acceptable salt thereofaccording to claim 1, wherein

is a single bond.
 12. The compound, or optical isomer, stereoisomer orisotopic variant thereof, or pharmaceutically acceptable salt thereofaccording to claim 1, wherein the heterocycle is a saturated orunsaturated, 4- to 8-membered hydrocarbon having 1 or 2 heteroatomsselected from N and
 0. 13. The compound, or optical isomer, stereoisomeror isotopic variant thereof, or pharmaceutically acceptable salt thereofaccording to claim 1, wherein the heterocycle is selected from the groupconsisting of tetrahydropyridine, dihydropyridine, piperidine,dihydropyran, tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane,azetidine, morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole,oxazepane, 2-oxa-5-azabicyclo[2.2.1]heptane, pyridyl, tetrahydrofuran,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane,2-oxa-7-azaspiro[3.4]octane, 2-azabicyclo[2.2.1]heptane,3-oxa-8-azabicyclo[3.2.1]octane, 3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine,3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2]-a]pyrazine, pyrimidine, pyrazole,2-oxa-7-azaspiro[3.5]nonane, and oxetane.
 14. The compound, or opticalisomer, stereoisomer or isotopic variant thereof, or pharmaceuticallyacceptable salt thereof according to claim 13, wherein the heterocycleis selected from the group consisting of tetrahydropyridine,dihydropyridine, piperidine, tetrahydropyran, pyrrolidine,2-oxa-6-azaspiroheptane, azetidine, morpholine,3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole,and oxetane.
 15. The compound, or optical isomer, stereoisomer orisotopic variant thereof, or pharmaceutically acceptable salt thereofaccording to claim 1, wherein the carbocycle is selected from the groupconsisting of cyclohexane, cyclohexene, cyclopropane, cyclobutane, andcyclopentane.
 16. The compound, or optical isomer, stereoisomer orisotopic variant thereof, or pharmaceutically acceptable salt thereofaccording to claim 13, wherein D is a direct bond, —O—, —C(═O)— or—C≡C—; R¹⁰ is halo, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl, halo-C₁-C₇ alkyl,saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated or unsaturated,4- to 10-membered heterocyclyl, or saturated or unsaturated, 4- to10-membered heterocyclyl-alkyl; the carbocycle or heterocycle may besubstituted with 1 to 5 substituents selected from hydroxy, halo,formyl, C₁-C₇ alkyl, hydroxy-C₁-C₇ alkyl, C₁-C₇ alkoxy-C₁-C₇ alkyl,halo-C₁-C₇ alkyl, C₁-C₇ alkylcarbonyl, C₁-C₇ alkoxycarbonyl, halo-C₁-C₇alkylcarbonyl, saturated or unsaturated C₃-C₁₀ carbocyclyl, saturated orunsaturated C₃-C₁₀ carbocyclylcarbonyl, (C₁-C₇ alkyl)(halo-C₁-C₇alkyl)amino, (C₁-C₇alkyl)(saturated or unsaturated, 4- to 10-memberedheterocyclyl)amino, and saturated or unsaturated, 4- to 10-memberedheterocyclyl-C₁-C₇ alkyl; the heterocycle is selected from the groupconsisting of tetrahydropyridine, dihydropyridine, piperidine,tetrahydropyran, pyrrolidine, 2-oxa-6-azaspiroheptane, azetidine,morpholine, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole, pyridyl,8-azabicyclo[3.2.1]octane, piperazine, 2-azaspiro[3.3]heptane, pyrazole,and oxetane; and the carbocycle is selected from the group consisting ofcyclohexane, cyclohexene, and cyclopropane.
 17. The compound, or opticalisomer, stereoisomer or isotopic variant thereof, or pharmaceuticallyacceptable salt thereof according to claim 1, wherein the compound isselected from the group consisting of:4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methoxy-2,3-dihydro-1,4-benzoxazepin-5-one;2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-methoxy-4,5-dihydro-3H-2-benzazepin-1-one;2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-hydroxy-4,5-dihydro-3H-2-benzazepin-1-one;2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(trifluoromethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-(trifluoromethoxy)-4,5-dihydro-3H-2-benzazepin-1-one;2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-7-ethoxy-4,5-dihydro-3H-2-benzazepin-1-one;[2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7yl]trifluoromethanesulfonate;2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-oxo-4,5-dihydro-3H-2-benzazepin-7-carbonitrile;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-isobutyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzoxazepin-5-one;tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,2,3,6-tetrahydropyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;8-(1-acetyl-3,6-dihydro-2H-pyridin-4-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(1-acetyl-4-piperidyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropyl-3,6-dihydro-2H-pyridin-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,6-dihydro-2H-pyran-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-piperidylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(dimethylamino)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(diethylaminomethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methyl-1-piperidyl)methy1]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-methoxyazetidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-methylmorpholin-4-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(4,4-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3,5-dimethyl-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-ylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxypyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-methylpyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)-1-piperidyl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methoxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,4-oxazepan-4-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-3-methyl-pyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-(hydroxymethyl)morpholin-4-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(3,3-difluoro-1-piperidyl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-hydroxy-1-piperidyl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethylpyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoropyrrolidin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(3,3-difluoropyrrolidin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylpiperazin-1-yl)methyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(2,6-dichloro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(2,3-difluoro-4-pyridyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-fluoro-3-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-tetrahydropyran-4-yloxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydropyran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;8-(cyclohexylmethoxy)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(tetrahydrofuran-2-ylmethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(1-acetyl-4-piperidyl)methoxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,2,2-trifluoroethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(dimethylamino)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-morpholinoethoxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(2-oxopyrrolidin-1-yl)ethoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(6-oxo-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;tert-butyl4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carboxylate;8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(1-acetyl-3-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(1-acetylpyrrolidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-propanoylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;8-[1-(cyclopropanecarbonyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;methyl3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3-dihydro-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carboxylate;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-isopropyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(1-cyclopropyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-ethylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-isopropylazetidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(oxetan-3-yl)azetidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethylazetidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-ethylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-pyridyloxy)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(2S)-1-isopropylpyrrolidin-2-yl]methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-methylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(4-ethylmorpholin-2-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-(morpholinomethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-6-fluoro-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(4-pyridylmethoxy)-3H-1,4-benzoxazepin-5-one;8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(morpholinomethyl)-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(3,3,3-trifluoropropyl)-2,3-dihydro-1,4-benzodiazepin-5-one;8-(cyclohexylmethyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-(cyclohexen-1-yl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[4-(trifluoromethyl)cyclohexen-1-yl]-2,3-dihydro-1,4-benzodiazepin-5-one; tert-butyl4-[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-5-oxo-2,3-dihydro-1,4-benzodiazepin-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate;8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-[(3R)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-[(3S)-1-acetylpyrrolidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-[(1-cyclobutyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-tetrahydrofuran-3-yl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[[1-(oxetan-3-yl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methylpyrrolidin-3-yl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-(1-methylpyrrolidin-3-yl)oxy-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(1-methyl-3-piperidyl)methoxy]-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-onedihydrochloride;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethyl-3-fluoro-4-piperidyl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-8-[(2-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzodiazepin-5-onedihydrochloride;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(5-fluoro-2-pyridyl)methoxy]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(4-piperidyloxy)-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-8-(1-acetylazetidin-3-yl)oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2,2-dimethyl-8-[(1-methyl-4-piperidyl)oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one;(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;2-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-fluoro-2,3-dihydro-1,4-benzoxazepin-5-one;8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[4,3-f][1,4]oxazepin-5-one;8-chloro-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one;7-chloro-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one;7-bromo-2-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-4,5-dihydro-3H-2-benzazepin-1-one;8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-methyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-2,3-dihydro-1,4-benzodiazepin-5-one;8-bromo-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-1-ethyl-3H-1,4-benzodiazepin-2,5-dione;2-[4-[[4-(2R)-3-(3,4,-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-5-oxo-2,3,-dihydro-1,4,-benzoxazepin-8-yl]-1-piperidyl]acetonitrile;8-[[1-(2,2-difluoroacetyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[[1-(2,2-difluoroacetyl)azetidin-3-yl]oxy-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydropyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[[1-[(3-methyloxetan-3-yl)methyl]-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-5-oxo-2,3-dihydro-1,4-benzoazepin-8-yl]oxy]piperidine-1-carbonitrile;8-[(4-acetylpiperazin-1-yl)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;3-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]azetidin-1-carbaldehyde;4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]methyl]piperazine-1-carbaldehyde;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(2-ethyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(8-acetyl-8-azabicyclo[3.2.1]octan-3-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[(2-acetyl-2-azaspiro[3.3]heptan-6-yl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(pyrrolidin-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(piperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;8-(3,3-difluoropyrrolidin-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-methylpiperazine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(pyrrolidin-1-ylmethyl)-3H-1,4-benzoxazepin-5-one;8-[(1-acetyl-4-piperidyl)oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;4-[[4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-5-oxo-3H-1,4-benzoxazepin-8-yl]oxy]piperidine-1-carbaldehyde;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[4-(oxetan-3-yl)piperazin-1-yl]methyl]-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-7-azaspiro[3.4]octan-7-ylmethyl)-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[4-(trifluoromethyl)piperidine-1-carbonyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2,6-dimethylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;8-(2-azabicyclo[2.2.1]heptane-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(2-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-methylmorpholin-4-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(morpholinomethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one;8-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-fluoropiperidine-1-carbonyl)-2,3-dihydro-1,4-benzoxazepin-5-one;8-(2,2-difluoromorpholin-4-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(4,4-difluoropiperidine-1-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-piperidylmethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[methyl(oxetan-3-yl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[4-[2-fluoroethyl(methyl)amino]cyclohexoxy]-2,3-dihydro-1,4-benzoxazepin-5-one;(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-ethanethiol-4-piperidyl)oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)azetidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2S)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-fluoroethyl)-4-piperidyl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-carbonyl)-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(2-oxa-5-azabicyclo[2.2.1]heptan-5-carbonyl)-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,5-dimethylmorpholin-4-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3-fluoro-1-methyl-4-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-fluoroethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;8-(3,4,6,7,8,8a-hexahydro-1H-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(5-fluoropyrimidin-2-yl)oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-propanoyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(cyclopropanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-(cyclopentanecarbonyl)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[(1-methyl-3-piperidyl)oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-morpholinoethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxypro-1-pynyl)-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-pipendyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(4-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(4-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[2-(3-pyridyl)ethynyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-hydroxybu-1-tynyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[3-(methylamino)pro-1-pynyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(3-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,3-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1-methylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(1,5-dimethylpyrazol-4-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[[(3R)-1-methyl-3-piperidyl]oxy]-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-fluoroethyl)-3-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(1-(2-hydroxy)-3-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxy-2-methyl-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-fluoro-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-ethoxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-hydroxy]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[8-2-fluoroethyl]-8-azabicyclo[3.2.1]octan-3-yl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-pyridyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-(6-methoxy-2-pyridyl)-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-(1-morpholinoethyl)-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-8-[1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl]-3H-pyrido[3,24][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxypropyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxypropyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride;(2R)-4-[(2R)-3-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[(3R,4R)-3-fluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride;8-[[3,3-difluoro-1-(2-hydroxyethyl)-4-piperidyl]oxy]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,2-dimethyl-3H-pyrido[3,24][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-hydroxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(4-methoxy-1-piperidyl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-8-[1-(3-hydroxy-3-methyl-pyrrolidin-1-yl)ethyl]-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-hydroxyethyl)-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-onedihydrochloride;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-(2-methoxyethyl)-4-piperidyl]oxy]-2,2-dimethyl-3H-pyrido[3,2-f][1,4]oxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3S)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3S)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3R)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolinon-2-yl)-2-hydroxy-propyl]-8-[(3S)-tetrahydrofuran-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2S)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[[1-[(2R)-2-hydroxypropyl]-4-piperidyl]oxy]-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;8-[cyclopropyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;8-[cyclopentyl(hydroxy)methyl]-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-2-methyl-8-[(3R)-1-methylpyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxy-propyl]-8-[(3R)-1-(2-methoxyethyl)pyrrolidin-3-yl]oxy-2-methyl-2,3-dihydro-1,4-benzoxazepin-5-one;4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-)-2-hydroxy-propyl]-2-methyl-8-[[1-(3,3,3-trifluoro-2-hydroxy-propyl)-4-piperidyl]oxy]-2,3-dihydro-1,4-benzoxazepin-5-one;and(2R)-4-[(2R)-3-(3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxypropyl]-2-methyl-8-[(3R)-1-(oxetan-3-yl)pyrrolidin-3-yl]oxy-2,3-dihydro-1,4-benzoxazepin-5-one.18. A method for treating a disease associated with protein argininemethyltransferase 5 (PRMT5) inhibition, comprising: administering to asubject in need thereof a therapeutically effective amount of thecompound, or pharmaceutically acceptable salt thereof of claim
 1. 19.The method according to claim 18, wherein the disease associated withPRMT5 inhibition is selected from cancer, blood disease, autoimmunedisease, inflammatory disease and neurodegenerative disease.
 20. Themethod according to claim 19, wherein the cancer is selected from thegroup consisting of acoustic neuroma, adenocarcinoma, adrenal cancer,anal cancer, angiosarcoma, benign monoclonal gammaglobulinopathy,cholangiocarcinoma, bladder cancer, breast cancer, brain cancer,lymphoma, multiple myeloma, lacrimal gland tumor, bronchial cancer,cervical cancer, craniopharyngioma, colorectal cancer, epithelialcarcinoma, epithelial cell tumor, endothelial sarcoma, endometrialcancer, esophageal cancer, Barrett's adenocarcinoma, Ewing's sarcoma,eye cancer, gallbladder cancer, gastric cancer, gastrointestinal stromaltumor (GIST), head and neck cancer, oral cancer (oral squamous cellcarcinoma, OSCC), throat cancer, hematopoietic cancer, hemangioblastoma,inflammatory myofibroblast tumor, immune cell amyloidosis, kidneycancer, liver cancer, lung cancer, myelodysplastic syndrome (MDS),mesothelioma, myeloproliferative disorder (MPD), chronic idiopathicmyelofibrosis, chronic myelogenous leukemia (CML), chronic neutrophilicleukemia (CNL), neuroblastoma, neurofibroma, neuroendocrine cancer,osteosarcoma, ovarian cancer, papillary adenocarcinoma, pancreaticcancer, penile cancer, prostate cancer, rectal cancer, rhabdomyosarcoma,salivary gland cancer, skin cancer, small intestine cancer, soft tissuesarcoma, thyroid cancer, urethral cancer, vaginal cancer and vulvarcancer.